rs72549401

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_003742.4(ABCB11):c.1723C>T(p.Arg575*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000229 in 1,612,812 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

ABCB11
NM_003742.4 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 2.29

Publications

11 publications found

Variant links:

Genes affected

ABCB11 (HGNC:42): (ATP binding cassette subfamily B member 11) 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. The protein encoded by this gene is the major canalicular bile salt export pump in man. Mutations in this gene cause a form of progressive familial intrahepatic cholestases which are a group of inherited disorders with severe cholestatic liver disease from early infancy. [provided by RefSeq, Jul 2008]

ABCB11 Gene-Disease associations (from GenCC):

progressive familial intrahepatic cholestasis type 2
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae)
benign recurrent intrahepatic cholestasis type 2
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ABCB11 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PVS1

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

PP5

Variant 2-168970131-G-A is Pathogenic according to our data. Variant chr2-168970131-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 6589.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCB11	NM_003742.4 link	c.1723C>T	p.Arg575*	stop_gained	Exon 15 of 28	ENST00000650372.1	NP_003733.2	O95342

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCB11	ENST00000650372.1 link	c.1723C>T	p.Arg575*	stop_gained	Exon 15 of 28		NM_003742.4	ENSP00000497931.1		O95342

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

151934

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00125

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

GnomAD2 exomes

AF:

0.0000402

AC:

AN:

248568

AF XY:

0.0000371

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000261

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000889

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000123

AC:

AN:

1460878

Hom.:

Cov.:

AF XY:

0.0000124

AC XY:

AN XY:

726748

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33418

American (AMR)

AF:

0.000224

AC:

AN:

44638

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26110

East Asian (EAS)

AF:

0.00

AC:

AN:

39670

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86228

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53394

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.00000630

AC:

AN:

1111354

Other (OTH)

AF:

0.00

AC:

AN:

60312

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.000125

AC:

AN:

151934

Hom.:

Cov.:

AF XY:

0.000202

AC XY:

AN XY:

74202

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41400

American (AMR)

AF:

0.00125

AC:

AN:

15218

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5144

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67954

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000907

ExAC

AF:

0.00000827

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Progressive familial intrahepatic cholestasis type 2

Pathogenic:2

Nov 01, 1998

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Jan 27, 2025

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:curation

The p.Arg575Ter variant in ABCB11 has been reported in many individuals with BSEP deficiency (PMID: 9806540, 17452236, 14988830, 18395098, 25847299, 28733223, 37168916), and has been identified in 0.05% (29/59856) of Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs72549401). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID: 6589) and has been interpreted as pathogenic by Invitae and OMIM. Of the affected individuals, five were compound heterozygotes that carried a reported pathogenic or likely pathogenic variant in trans or with unknown phase, which increases the likelihood that the p.Arg575Ter variant is pathogenic (Variation ID: 501601, 595313; PMID: 17452236, 18395098). This nonsense variant leads to a premature termination codon at position 575, which is predicted to lead to a truncated or absent protein. Computational tools predict a splicing impact of in-frame exon skipping, though this information is not predictive enough to rule out pathogenicity. Loss of function of the ABCB11 gene is an established disease mechanism in autosomal recessive BSEP deficiency. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive BSEP deficiency. ACMG/AMP Criteria applied: PVS1_strong, PM3_strong (Richards 2015). -

ABCB11-related disorder

Pathogenic:1

Aug 06, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The ABCB11 c.1723C>T variant is predicted to result in premature protein termination (p.Arg575*). This variant has been reported with a second ABCB11 variant or in the homozygous state in individuals with familial progressive intrahepatic cholestasis (Strautnieks et al 1998. PubMed ID: 9806540; Schiemann et al. 2007. PubMed ID: 17452236; Table S3, Hertel et al. 2021. PubMed ID: 34016879) or benign recurrent intrahepatic cholestasis (Kato et al. 2023. PubMed ID: 37762919). This variant is reported in 0.026% of alleles in individuals of Latino descent in gnomAD. Nonsense variants in ABCB11 are expected to be pathogenic. This variant is interpreted as pathogenic. -

Benign recurrent intrahepatic cholestasis type 2

Pathogenic:1

Mar 28, 2024

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

See cases

Pathogenic:1

Oct 14, 2024

Institute of Human Genetics, University Hospital Muenster

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG categories: PVS1,PS4,PM2_sup,PM3_sup -

Benign recurrent intrahepatic cholestasis type 2;C3489789:Progressive familial intrahepatic cholestasis type 2

Pathogenic:1

May 23, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:1

Feb 14, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Arg575*) in the ABCB11 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ABCB11 are known to be pathogenic (PMID: 18395098, 20232290). This variant is present in population databases (rs72549401, gnomAD 0.03%). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 6589). This premature translational stop signal has been observed in individual(s) with progressive familial intrahepatic cholestasis (PMID: 9806540). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.42

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

0.75

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Uncertain

0.90

PhyloP100

2.3

Vest4

0.89

GERP RS

5.3

PromoterAI

-0.075

Neutral

(source)

Mutation Taster

=0/200

disease causing (ClinVar)

(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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over