rs58238559

Variant names:

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_000443.4(ABCB4):c.523A>G(p.Thr175Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00933 in 1,613,900 control chromosomes in the GnomAD database, including 146 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0091 ( 12 hom., cov: 31)

Exomes 𝑓: 0.0094 ( 134 hom. )

Consequence

ABCB4
NM_000443.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1B:12

Conservation

PhyloP100: 5.09

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 Benign. Variant got -19 ACMG points.

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.

BP4

Computational evidence support a benign effect (MetaRNN=0.011848539).

BP6

Variant 7-87452957-T-C is Benign according to our data. Variant chr7-87452957-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 13691.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-87452957-T-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00909 (1385/152306) while in subpopulation SAS AF= 0.012 (58/4830). AF 95% confidence interval is 0.00954. There are 12 homozygotes in gnomad4. There are 768 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 12 SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCB4	NM_000443.4 link	c.523A>G	p.Thr175Ala	missense_variant	Exon 6 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.523A>G	p.Thr175Ala	missense_variant	Exon 6 of 28		NM_000443.4	ENSP00000496956.2		P21439-2

Frequencies

GnomAD3 genomes

AF:

0.00910

AC:

1385

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00128

Gnomad AMI

AF:

0.00987

Gnomad AMR

AF:

0.00733

Gnomad ASJ

AF:

0.00346

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0122

Gnomad FIN

AF:

0.0418

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0100

Gnomad OTH

AF:

0.00574

GnomAD3 exomes

AF:

0.0113

AC:

2847

AN:

251274

Hom.:

AF XY:

0.0117

AC XY:

1595

AN XY:

135796

show subpopulations

Gnomad AFR exome

AF:

0.00148

Gnomad AMR exome

AF:

0.00828

Gnomad ASJ exome

AF:

0.00526

Gnomad EAS exome

AF:

0.000598

Gnomad SAS exome

AF:

0.0130

Gnomad FIN exome

AF:

0.0382

Gnomad NFE exome

AF:

0.0105

Gnomad OTH exome

AF:

0.00816

GnomAD4 exome

AF:

0.00936

AC:

13680

AN:

1461594

Hom.:

134

Cov.:

AF XY:

0.00964

AC XY:

7007

AN XY:

727118

show subpopulations

Gnomad4 AFR exome

AF:

0.00125

Gnomad4 AMR exome

AF:

0.00781

Gnomad4 ASJ exome

AF:

0.00509

Gnomad4 EAS exome

AF:

0.000655

Gnomad4 SAS exome

AF:

0.0136

Gnomad4 FIN exome

AF:

0.0353

Gnomad4 NFE exome

AF:

0.00862

Gnomad4 OTH exome

AF:

0.00760

GnomAD4 genome

AF:

0.00909

AC:

1385

AN:

152306

Hom.:

Cov.:

AF XY:

0.0103

AC XY:

768

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.00128

Gnomad4 AMR

AF:

0.00739

Gnomad4 ASJ

AF:

0.00346

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.0120

Gnomad4 FIN

AF:

0.0418

Gnomad4 NFE

AF:

0.0100

Gnomad4 OTH

AF:

0.00568

Alfa

AF:

0.00909

Hom.:

Bravo

AF:

0.00598

TwinsUK

AF:

0.0102

AC:

ALSPAC

AF:

0.00701

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.0120

AC:

103

ExAC

AF:

0.0106

AC:

1288

Asia WGS

AF:

0.00462

AC:

AN:

3478

EpiCase

AF:

0.00867

EpiControl

AF:

0.00771

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jan 06, 2016

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ABCB4: BP4, BS1, BS2 -

Apr 24, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 23022423, 26474921, 28776642, 25888430, 26153658, 20163776, 23533021, 25333069, 22331132, 11313316, 27884173, 28176361, 28924228, 29761167, 31335238, 31538484) -

not specified

Benign:4

Feb 18, 2022

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

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jun 03, 2016

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency in ESP (all): 110/13006=8.45%; Frequency in ESP (EA): 103/8600=1.19% -

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Progressive familial intrahepatic cholestasis type 3

Benign:2

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

May 18, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Low phospholipid associated cholelithiasis

Pathogenic:1

May 01, 2001

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Cholestasis, intrahepatic, of pregnancy, 3

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Uncertain

0.060

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.77

.;.;D;.;.

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

.;D;D;D;.

MetaRNN

Benign

0.012

T;T;T;T;T

MetaSVM

Uncertain

0.16

MutationAssessor

Uncertain

2.8

M;M;M;M;M

PrimateAI

Uncertain

0.49

PROVEAN

Uncertain

-3.8

.;D;D;D;D

REVEL

Uncertain

0.58

Sift

Uncertain

0.0020

.;D;D;D;D

Sift4G

Benign

0.083

.;T;T;T;T

Polyphen

0.84

P;.;P;P;.

Vest4

0.32, 0.48, 0.47, 0.23

MPC

0.78

ClinPred

0.027

GERP RS

5.9

Varity_R

0.78

gMVP

0.89

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