rs2230028

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_000443.4(ABCB4):c.1954A>G(p.Arg652Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0895 in 1,613,710 control chromosomes in the GnomAD database, including 9,653 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.15 ( 2931 hom., cov: 32)

Exomes 𝑓: 0.083 ( 6722 hom. )

Consequence

ABCB4
NM_000443.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.941

Publications

52 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=0.0030877888).

BP6

Variant 7-87426860-T-C is Benign according to our data. Variant chr7-87426860-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256160.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.341 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCB4	NM_000443.4 link	c.1954A>G	p.Arg652Gly	missense_variant	Exon 16 of 28	ENST00000649586.2	NP_000434.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCB4	ENST00000649586.2 link	c.1954A>G	p.Arg652Gly	missense_variant	Exon 16 of 28		NM_000443.4	ENSP00000496956.2

Frequencies

GnomAD3 genomes

AF:

0.153

AC:

23204

AN:

151950

Hom.:

2907

Cov.:

show subpopulations

Gnomad AFR

AF:

0.345

Gnomad AMI

AF:

0.0921

Gnomad AMR

AF:

0.0958

Gnomad ASJ

AF:

0.0950

Gnomad EAS

AF:

0.0269

Gnomad SAS

AF:

0.136

Gnomad FIN

AF:

0.0737

Gnomad MID

AF:

0.104

Gnomad NFE

AF:

0.0767

Gnomad OTH

AF:

0.129

GnomAD2 exomes

AF:

0.0998

AC:

25065

AN:

251072

AF XY:

0.0968

show subpopulations

Gnomad AFR exome

AF:

0.354

Gnomad AMR exome

AF:

0.0899

Gnomad ASJ exome

AF:

0.0900

Gnomad EAS exome

AF:

0.0266

Gnomad FIN exome

AF:

0.0725

Gnomad NFE exome

AF:

0.0737

Gnomad OTH exome

AF:

0.102

GnomAD4 exome

AF:

0.0829

AC:

121131

AN:

1461642

Hom.:

6722

Cov.:

AF XY:

0.0837

AC XY:

60883

AN XY:

727104

show subpopulations

African (AFR)

AF:

0.355

AC:

11894

AN:

33468

American (AMR)

AF:

0.0914

AC:

4089

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0917

AC:

2397

AN:

26130

East Asian (EAS)

AF:

0.0225

AC:

893

AN:

39674

South Asian (SAS)

AF:

0.136

AC:

11711

AN:

86246

European-Finnish (FIN)

AF:

0.0736

AC:

3930

AN:

53386

Middle Eastern (MID)

AF:

0.0794

AC:

458

AN:

5768

European-Non Finnish (NFE)

AF:

0.0720

AC:

80045

AN:

1111870

Other (OTH)

AF:

0.0946

AC:

5714

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

5968

11936

17904

23872

29840

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3128

6256

9384

12512

15640

<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:

0.153

AC:

23279

AN:

152068

Hom.:

2931

Cov.:

AF XY:

0.151

AC XY:

11232

AN XY:

74356

show subpopulations

African (AFR)

AF:

0.345

AC:

14303

AN:

41408

American (AMR)

AF:

0.0957

AC:

1463

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.0950

AC:

330

AN:

3472

East Asian (EAS)

AF:

0.0268

AC:

139

AN:

5184

South Asian (SAS)

AF:

0.137

AC:

659

AN:

4824

European-Finnish (FIN)

AF:

0.0737

AC:

781

AN:

10592

Middle Eastern (MID)

AF:

0.109

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0767

AC:

5213

AN:

67992

Other (OTH)

AF:

0.130

AC:

275

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

893

1786

2678

3571

4464

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

240

480

720

960

1200

<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:

0.0990

Hom.:

4754

Bravo

AF:

0.160

TwinsUK

AF:

0.0782

AC:

290

ALSPAC

AF:

0.0703

AC:

271

ESP6500AA

AF:

0.343

AC:

1513

ESP6500EA

AF:

0.0790

AC:

679

ExAC

AF:

0.105

AC:

12793

Asia WGS

AF:

0.100

AC:

346

AN:

3478

EpiCase

AF:

0.0781

EpiControl

AF:

0.0745

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Jan 08, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Dec 03, 2021

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 13, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Progressive familial intrahepatic cholestasis type 3

Benign:2

May 31, 2018

SIB Swiss Institute of Bioinformatics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:curation

This variant is interpreted as a Benign - Stand Alone, for PFIC3, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: BA1 => Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. BS2 => Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age. -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: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). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Cholestasis, intrahepatic, of pregnancy, 3

Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.51

CADD

Benign

8.6

(source)

DANN

Benign

0.44

DEOGEN2

Benign

0.25

.;.;T;.;.

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.00063

LIST_S2

Benign

0.047

.;T;T;T;.

MetaRNN

Benign

0.0031

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.31

N;N;N;N;N

PhyloP100

0.94

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.050

.;N;N;N;N

REVEL

Benign

0.23

Sift

Benign

0.34

.;T;T;T;T

Sift4G

Benign

0.38

.;T;T;T;T

Polyphen

0.0

B;.;B;B;.

Vest4

0.020, 0.031, 0.019

MPC

0.35

ClinPred

0.00072

GERP RS

1.1

Varity_R

0.039

gMVP

0.31

Mutation Taster

=100/0

polymorphism (auto)

(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