7-87440230-T-C

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 13P and 1B. PM1PM2PP2PP5_Very_StrongBP4

The NM_000443.4(ABCB4):c.1529A>G(p.Asn510Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000193 in 1,614,190 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00020 ( 1 hom. )

Consequence

ABCB4
NM_000443.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14U:1

Conservation

PhyloP100: 5.12

Variant links:

Genes affected

ABCB4 (HGNC:45): (ATP binding cassette subfamily B member 4) The membrane-associated protein encoded by this gene is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White). This protein is a member of the MDR/TAP subfamily. Members of the MDR/TAP subfamily are involved in multidrug resistance as well as antigen presentation. This gene encodes a full transporter and member of the p-glycoprotein family of membrane proteins with phosphatidylcholine as its substrate. The function of this protein has not yet been determined; however, it may involve transport of phospholipids from liver hepatocytes into bile. Alternative splicing of this gene results in several products of undetermined function. [provided by RefSeq, Jul 2008]

ABCB4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PM1

In a domain ABC transporter 1 (size 236) in uniprot entity MDR3_HUMAN there are 29 pathogenic changes around while only 1 benign (97%) in NM_000443.4

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the ABCB4 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 32 curated pathogenic missense variants (we use a threshold of 10). The gene has 6 curated benign missense variants. Gene score misZ: 1.9749 (below the threshold of 3.09). Trascript score misZ: 3.5425 (above the threshold of 3.09). GenCC associations: The gene is linked to pancreatitis, low phospholipid associated cholelithiasis, progressive familial intrahepatic cholestasis type 3.

PP5

Variant 7-87440230-T-C is Pathogenic according to our data. Variant chr7-87440230-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 291252.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.25034124). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCB4	NM_000443.4 link	c.1529A>G	p.Asn510Ser	missense_variant	Exon 13 of 28	ENST00000649586.2	NP_000434.1	P21439-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCB4	ENST00000649586.2 link	c.1529A>G	p.Asn510Ser	missense_variant	Exon 13 of 28		NM_000443.4	ENSP00000496956.2		P21439-2

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000199

AC:

AN:

251250

Hom.:

AF XY:

0.000265

AC XY:

AN XY:

135824

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.000397

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.000621

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000200

AC:

292

AN:

1461832

Hom.:

Cov.:

AF XY:

0.000237

AC XY:

172

AN XY:

727214

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000134

Gnomad4 ASJ exome

AF:

0.000191

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.000696

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000172

Gnomad4 OTH exome

AF:

0.000348

GnomAD4 genome

AF:

0.000125

AC:

AN:

152358

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74510

show subpopulations

Gnomad4 AFR

AF:

0.0000240

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000206

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000291

Hom.:

Bravo

AF:

0.000185

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000181

AC:

Asia WGS

AF:

0.00260

AC:

AN:

3476

EpiCase

AF:

0.000218

EpiControl

AF:

0.000237

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4Uncertain:1

Apr 08, 2022

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 17, 2018

Eurofins Ntd Llc (ga)

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 25, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

- -

Sep 06, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 510 of the ABCB4 protein (p.Asn510Ser). This variant is present in population databases (rs375315619, gnomAD 0.06%), including at least one homozygous and/or hemizygous individual. This missense change has been observed in individuals with autosomal recessive progressive familial intrahepatic cholestasis type 3 and/or intrahepatic cholestasis of pregnancy (PMID: 23022423, 23533021, 26324191, 26474921, 28776642, 32581362, 32917322, 34376370). ClinVar contains an entry for this variant (Variation ID: 291252). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Possibly Damaging". The serine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Studies have shown that this missense change alters ABCB4 gene expression (PMID: 26474921). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Aug 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ABCB4: PM3:Very Strong, PM2, PP4, PS3:Supporting -

Progressive familial intrahepatic cholestasis type 3

Pathogenic:4

Aug 12, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 04, 2025

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 01, 2024

3billion

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.018%). Predicted Consequence/Location: Missense variant Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000291252 /PMID: 20422496). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -

Feb 14, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cholestasis, intrahepatic, of pregnancy, 3

Pathogenic:2

Aug 12, 2023

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

ABCB4-related disorder

Pathogenic:1

Aug 28, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ABCB4 c.1529A>G variant is predicted to result in the amino acid substitution p.Asn510Ser. In the heterozygous state alone, this variant was reported in patients with intrahepatic cholestasis of pregnancy (ICP) (Anzivino. 2013. PubMed ID: 23022423; Poupon. 2013. PubMed ID: 23533021; Falcão. 2021. PubMed ID: 34376370; Stalke 2017. PubMed ID: 28776642). In the compound heterozygous state with another pathogenic ABCB4 variant, this variant was reported to cause progressive familial intrahepatic cholestasis (PFIC) (Delaunay. 2015. PubMed ID: 26474921; Davit-Spraul. 2010. PubMed ID: 20422496; Falcão. 2021. PubMed ID: 34376370). Functional assays in the Delaunay study indicated the p.Asn510Ser change reduced protein stability. This variant is reported in 0.062% of alleles in individuals of South Asian descent in gnomAD. This variant is interpreted as likely pathogenic. -

Progressive familial intrahepatic cholestasis

Pathogenic:1

Dec 14, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ABCB4 c.1529A>G (p.Asn510Ser) results in a conservative amino acid change located in the first ATP-binding domain (IPR003439) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0002 in 251250 control chromosomes, predominantly at a frequency of 0.00062 within the South Asian subpopulation in the gnomAD database, including 1 homozygote. This frequency is not higher than the estimated maximum expected for a pathogenic variant in ABCB4 causing Familial Intrahepatic Cholestasis (0.0022), allowing no conclusion about variant significance. The variant, c.1529A>G, has been reported in the literature in (presumed) compound heterozygous state together with a second (likely) pathogenic variant in individuals affected with hepatobiliary disease and intrahepatic cholestasis of pregnancy (e.g. Delaunay_2016, Stalke_2018, Falcao_2022). The variant has been also reported in (apparent) heterozygosity in affected individuals in whom a second (likely) pathogenic mutation was not identified. These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, and demonstrated decreased protein stability (Delaunay_2016). The following publications have been ascertained in the context of this evaluation (PMID: 32917322, 26324191, 26474921, 28587926, 32626542, 28776642, 19467940, 34376370). Eight other submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant with conflicting assessments, i.e. as pathogenic (n=3), likely pathogenic (n=4), or VUS (n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Progressive familial intrahepatic cholestasis type 1

Pathogenic:1

May 28, 2019

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Progressive familial intrahepatic cholestasis type 3;C2609268:Low phospholipid associated cholelithiasis;C3554241:Cholestasis, intrahepatic, of pregnancy, 3

Pathogenic:1

Apr 29, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.090

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.89

.;.;D;.;.

Eigen

Benign

0.16

Eigen_PC

Benign

0.15

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.94

.;D;D;D;.

M_CAP

Pathogenic

0.39

MetaRNN

Benign

0.25

T;T;T;T;T

MetaSVM

Uncertain

0.39

MutationAssessor

Benign

0.38

N;N;N;N;N

PrimateAI

Benign

0.43

PROVEAN

Pathogenic

-4.5

.;D;D;D;D

REVEL

Uncertain

0.57

Sift

Uncertain

0.0010

.;D;D;D;D

Sift4G

Uncertain

0.0030

.;D;D;D;D

Polyphen

0.86

P;.;P;P;.

Vest4

0.70, 0.60, 0.62, 0.69

MVP

0.88

MPC

0.58

ClinPred

0.31

GERP RS

2.1

Varity_R

0.92

gMVP

0.75

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over