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Table 2 Novel ABCB4 variants and the pathogenicity classification

From: Clinical and genetic characterization of pediatric patients with progressive familial intrahepatic cholestasis type 3 (PFIC3): identification of 14 novel ABCB4 variants and review of the literatures

Patient

No

Nucleotide changes

Amino acid changes

Variant types

ACMG evidences

ACMG classification

Allele Frequency

In silico verdict

1000 Genomes

gnomAD

Mutation

Taster

PolyPhen-2

PROVEAN

HSF

NNsplice

1

c.2782A > G

p.Arg928Gly

Missense

PM2 + PM3 + PP1-4

Likely pathogenic

NI

NI

D

ProbD

D

–

–

1

c.136-2A > G

–

Splicing

PVS1 + PM2 + PP1 + PP3 + PP4

Pathogenic

NI

NI

–

–

–

S

S

2/3

c.1645C > T

p.Arg549Cys

Missense

PM2 + PM3 + PP1-4

Likely pathogenic

NI

NI

D

ProbD

D

–

–

4

c.1801G > A

p.Ala601Thr

Missense

PM2 + PP1-4

Likely pathogenic

NI

0.007962‰

D

PossD

D

–

–

4

c.1406G > A

p.Arg469Lys

Missense

PM2 + PP1-4

Likely pathogenic

NI

NI

D

ProbD

D

–

–

7

c.3100_3101insA

p.Ile1034Asnfs*4

Frameshift

PVS1 + PM2 + PP1 + PP4

Pathogenic

NI

NI

–

–

–

–

 

7

c.80 + 1G > C

–

Splicing

PVS1 + PM2 + PP1 + PP3 + PP4

Pathogenic

NI

NI

–

–

–

S

S

8

c.716C > T

p.Ser239Leu

Missense

PM2 + PM3 + PP1-4

Likely pathogenic

NI

NI

D

ProbD

D

–

–

9

c.3230C > T

p.Thr1077Met

Missense

PM2 + PM3 + PP1-4

Likely pathogenic

NI

0.1991‰

D

ProbD

D

–

–

10

c.2914G > A

p.Asp972Asn

Missense

PM2 + PP1-4

Likely pathogenic

NI

NI

D

B

N

–

–

10

c.965 T > C

p.Leu322Pro

Missense

PM2 + PP1-4

Likely pathogenic

NI

NI

D

ProbD

D

–

–

12

c.2123G > A

p.Trp708*

Nonsense

PVS1 + PM2 + PP1 + PP4

Pathogenic

NI

NI

–

–

–

–

–

12

c.3789delA

p.Gly1264Alafs*38

Frameshift

PVS1 + PM2 + PP1 + PP4

Pathogenic

NI

NI

D

–

–

–

–

13

c.879dupA

p.Ala294Serfs*62

Frameshift

PVS1 + PM2 + PP1 + PP4

Pathogenic

NI

NI

–

–

–

–

–

  1. According to the ACMG criteria [35]: PVS1, null variant (nonsense, frameshift, canonical ± 1 or 2 ss, etc.) in a gene where loss of function is a known mechanism of disease; PM2, absent from controls (or at extremely low frequency if recessive) absent from controls in 1000 Genomes Project, or gnomAD; PM3, for recessive disorders, detected in trans with a pathogenic variant; PP1, co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease; PP2, missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease; PP3, multiple lines of computational evidence support a deleterious effect on the gene or gene product; PP4, patient’s phenotype or family history is highly specific for a disease with a single genetic etiology; -, not applicable; NI not included; D disease causing/deleterious; PossD possibly damaging; ProbD probably damaging; B benign; N neutral/not affecting; S splicing potential alteration of splicing, HSF human splicing finder