rs2230028

Positions:

Variant summary

Our verdict is Benign. Variant got -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. 15/20 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

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 gene, where missense usually causes diseases (based on misZ statistic), ABCB4. . Gene score misZ: 1.9749 (greater than the threshold 3.09). Trascript score misZ: 3.5425 (greater than threshold 3.09). The gene has 32 curated pathogenic missense variants (we use a threshold of 10). The gene has 6 curated benign missense variants. GenCC has associacion of the gene with pancreatitis, low phospholipid associated cholelithiasis, progressive familial intrahepatic cholestasis type 3.

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 [Likely_benign]. Clinvar id 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/exons	MANE	Protein	UniProt
ABCB4	NM_000443.4 link	c.1954A>G	p.Arg652Gly	missense_variant	16/28	ENST00000649586.2	NP_000434.1	P21439-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCB4	ENST00000649586.2 link	c.1954A>G	p.Arg652Gly	missense_variant	16/28		NM_000443.4	ENSP00000496956.2		P21439-2

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

GnomAD3 exomes

AF:

0.0998

AC:

25065

AN:

251072

Hom.:

1981

AF XY:

0.0968

AC XY:

13141

AN XY:

135696

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 SAS exome

AF:

0.139

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

Gnomad4 AFR exome

AF:

0.355

Gnomad4 AMR exome

AF:

0.0914

Gnomad4 ASJ exome

AF:

0.0917

Gnomad4 EAS exome

AF:

0.0225

Gnomad4 SAS exome

AF:

0.136

Gnomad4 FIN exome

AF:

0.0736

Gnomad4 NFE exome

AF:

0.0720

Gnomad4 OTH exome

AF:

0.0946

GnomAD4 genome

AF:

0.153

AC:

23279

AN:

152068

Hom.:

2931

Cov.:

AF XY:

0.151

AC XY:

11232

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.345

Gnomad4 AMR

AF:

0.0957

Gnomad4 ASJ

AF:

0.0950

Gnomad4 EAS

AF:

0.0268

Gnomad4 SAS

AF:

0.137

Gnomad4 FIN

AF:

0.0737

Gnomad4 NFE

AF:

0.0767

Gnomad4 OTH

AF:

0.130

Alfa

AF:

0.0865

Hom.:

1498

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

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 08, 2016	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. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 03, 2021	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 13, 2016	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Progressive familial intrahepatic cholestasis type 3

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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. -
Benign, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	May 31, 2018	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. -

Cholestasis, intrahepatic, of pregnancy, 3

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

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. -

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

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

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

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