rs121918440

chr7-87411948-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000443.4(ABCB4):c.2869C>T(p.Arg957Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,613,706 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

ABCB4
NM_000443.4 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 2.27

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 18 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 7-87411948-G-A is Pathogenic according to our data. Variant chr7-87411948-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 13687.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-87411948-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCB4	NM_000443.4 linkuse as main transcript	c.2869C>T	p.Arg957Ter	stop_gained	23/28	ENST00000649586.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCB4	ENST00000649586.2 linkuse as main transcript	c.2869C>T	p.Arg957Ter	stop_gained	23/28		NM_000443.4	P1	P21439-2
ABCB4	ENST00000265723.8 linkuse as main transcript	c.2869C>T	p.Arg957Ter	stop_gained	23/28	1			P21439-1
ABCB4	ENST00000359206.8 linkuse as main transcript	c.2869C>T	p.Arg957Ter	stop_gained	23/28	1		P1	P21439-2
ABCB4	ENST00000453593.5 linkuse as main transcript	c.2783+1669C>T		intron_variant		5			P21439-3

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461566

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727076

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000180

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152140

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74322

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000324

Hom.:

Bravo

AF:

0.0000151

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Feb 03, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jun 25, 2023	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 13687). This premature translational stop signal has been observed in individual(s) with familial intrahepatic cholestasis (PMID: 9419367). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg957*) in the ABCB4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ABCB4 are known to be pathogenic (PMID: 17726488, 25755532). -

Cholestasis, intrahepatic, of pregnancy, 3

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 18, 2017

- -

Low phospholipid associated cholelithiasis

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Dec 13, 2018

The ABCB4 c.2869C>T (p.Arg957Ter) variant is a stop-gained variant that is predicted to result in a premature termination of the protein. The p.Arg957Ter variant has been reported in two studies and is found in two probands with progressive familial intrahepatic cholestasis, including one in a homozygous state and one in a compound heterozygous state (de Vree et al. 1998; Stalke et al. 2017). Canalicular staining for ABCB4 protein was negative in liver tissue of the homozygous proband, and Northern blot and Western blot analysis showed low level or absence of RNA and protein (de Vree et al. 1998). The homozygous proband was from a consanguineous family and no other probands with liver disease were reported in this family, except for the mother who had experienced episodes of cholestasis during pregnancy (de Vree et al. 1998). Control data are unavailable for this variant and it is not found in the 1000 Genomes Project, the Exome Sequencing Project, the Exome Aggregation Consortium, or the Genome Aggregation Database. Based on the evidence and potential impact of stop-gained variants, this variant is classified as likely pathogenic for ABCB4-related intrahepatic cholestasis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Progressive familial intrahepatic cholestasis type 3

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 18, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.58

Cadd

Pathogenic

Dann

Uncertain

1.0

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Uncertain

0.87

MutationTaster

Benign

1.0

A;A;A;A;A

Vest4

0.90

GERP RS

3.7

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