rs58238559

Variant names:

Variant summary

Our verdict is Benign. The variant received -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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T175M) has been classified as Uncertain significance.

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

Publications

33 publications found

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 Gene-Disease associations (from GenCC):

progressive familial intrahepatic cholestasis type 3
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet
gallbladder disease 1
Inheritance: SD, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
pancreatitis
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ABCB4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 gallbladder disease 1, progressive familial intrahepatic cholestasis type 3, pancreatitis.

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 CliVar as Benign/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 CliVar as Benign/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 CliVar as Benign/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 CliVar as Benign/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 CliVar as Benign/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 CliVar as Benign/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 CliVar as Benign/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 CliVar as Benign/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 CliVar as Benign/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 CliVar as Benign/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 CliVar as Benign/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 CliVar as Benign/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 CliVar as Benign/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 CliVar as Benign/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 CliVar as Benign/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 CliVar as Benign/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 CliVar as Benign/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 CliVar as Benign/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 CliVar as Benign/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 CliVar as Benign/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 CliVar as Benign/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 CliVar as Benign/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 CliVar as Benign/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 CliVar as Benign/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 CliVar as Benign/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 CliVar as Benign/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 CliVar as Benign/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 CliVar as Benign/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 CliVar as Benign/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 CliVar as Benign/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 CliVar as Benign/Likely_benign. Clinvar id is 13691.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 12 SD,AR,AD 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

GnomAD2 exomes

AF:

0.0113

AC:

2847

AN:

251274

AF XY:

0.0117

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 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

African (AFR)

AF:

0.00125

AC:

AN:

33476

American (AMR)

AF:

0.00781

AC:

349

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.00509

AC:

133

AN:

26132

East Asian (EAS)

AF:

0.000655

AC:

AN:

39688

South Asian (SAS)

AF:

0.0136

AC:

1174

AN:

86248

European-Finnish (FIN)

AF:

0.0353

AC:

1887

AN:

53406

Middle Eastern (MID)

AF:

0.00468

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00862

AC:

9583

AN:

1111774

Other (OTH)

AF:

0.00760

AC:

459

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.448

Heterozygous variant carriers

696

1391

2087

2782

3478

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

326

652

978

1304

1630

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00909

AC:

1385

AN:

152306

Hom.:

Cov.:

AF XY:

0.0103

AC XY:

768

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.00128

AC:

AN:

41564

American (AMR)

AF:

0.00739

AC:

113

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00346

AC:

AN:

3472

East Asian (EAS)

AF:

0.000386

AC:

AN:

5184

South Asian (SAS)

AF:

0.0120

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0418

AC:

443

AN:

10608

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0100

AC:

682

AN:

68028

Other (OTH)

AF:

0.00568

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

142

213

284

355

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00943

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

May 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ABCB4: BP4, BS1, BS2 -

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

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Jun 03, 2016

Eurofins Ntd Llc (ga)

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

- -

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

May 18, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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. -

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

(source)

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

PhyloP100

5.1

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

Mutation Taster

=91/9

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over