rs72549395

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_003742.4(ABCB11):c.3457C>T(p.Arg1153Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,613,684 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1153H) has been classified as Pathogenic.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

ABCB11
NM_003742.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13

Conservation

PhyloP100: 1.72

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 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PM1

In a topological_domain Cytoplasmic (size 288) in uniprot entity ABCBB_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_003742.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr2-168927316-C-T is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.95

PP5

Variant 2-168927317-G-A is Pathogenic according to our data. Variant chr2-168927317-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 288726.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-168927317-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCB11	NM_003742.4 link	c.3457C>T	p.Arg1153Cys	missense_variant	26/28	ENST00000650372.1	NP_003733.2	O95342

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ABCB11	ENST00000650372.1 link	c.3457C>T	p.Arg1153Cys	missense_variant	26/28		NM_003742.4	ENSP00000497931.1	O95342
ABCB11	ENST00000649448.1 link	c.1834C>T	p.Arg612Cys	missense_variant	13/15			ENSP00000497165.1	A0A3B3IS78
ABCB11	ENST00000439188.1 link	n.*1882-27C>T		intron_variant		2		ENSP00000416058.1	H7C486

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152110

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

249172

Hom.:

AF XY:

0.0000222

AC XY:

AN XY:

135176

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000464

Gnomad NFE exome

AF:

0.00000885

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.00000821

AC:

AN:

1461574

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

727070

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.00000630

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152110

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74304

show subpopulations

Gnomad4 AFR

AF:

0.0000483

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:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000301

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:6

Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 30, 2024	Published functional studies demonstrate this variant results in impaired transport activity and protein expression as compared to wild-type (PMID: 20010382, 12370274); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 19101985, 32808743, 18798335, 10579978, 17947449, 17241866, 28119944, 20422495, 9806540, 25085279, 26678486, 28733223, 20232290, 27050426, 18395098, 20683201, 32289814, 34016879, 35257483, 34961929, 12370274, 33915153, 26382629, 20010382) -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 14, 2017	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 18, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 11, 2023	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg1153 amino acid residue in ABCB11. Other variant(s) that disrupt this residue have been observed in individuals with ABCB11-related conditions (PMID: 18395098, 26678486), which suggests that this may be a clinically significant amino acid residue. Experimental studies have shown that this missense change affects ABCB11 function (PMID: 12370274, 18798335). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ABCB11 protein function. ClinVar contains an entry for this variant (Variation ID: 288726). This missense change has been observed in individuals with familial intrahepatic cholestasis (PMID: 9806540, 18395098, 20232290, 26678486, 27050426). This variant is present in population databases (rs72549395, gnomAD 0.004%). This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 1153 of the ABCB11 protein (p.Arg1153Cys). -

Progressive familial intrahepatic cholestasis type 2

Pathogenic:4

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Aug 18, 2020	- -
Pathogenic, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 14, 2024	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 04, 2020	This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
Pathogenic, no assertion criteria provided	clinical testing	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	Jan 29, 2019	- -

ABCB11-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 01, 2023

The ABCB11 c.3457C>T variant is predicted to result in the amino acid substitution p.Arg1153Cys. This variant has been reported as causative for intrahepatic cholestasis (Strautnieks et al. 1998. PubMed ID: 9806540; Al-Hussaini et al. 2021. PubMed ID: 33915153; Bakır et al. 2021. PubMed ID: 34961929). Functional studies have shown that the p.Arg1153Cys substitutions prevents proper protein localization and function (Wang et al. 2002. PubMed ID: 12370274; Byrne et al. 2009. PubMed ID: 19101985). An alternate substitution of this amino acid (p.Arg1153His) has also been reported in individuals with intrahepatic cholestasis (Strautnieks et al. 2008. PubMed ID: 18395098). This variant is reported in 0.0041% of alleles in individuals of African descent in gnomAD. Given the evidence, we interpret c.3457C>T (p.Arg1153Cys) as pathogenic. -

Benign recurrent intrahepatic cholestasis type 2

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Mar 02, 2024

- -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 10, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.53

BayesDel_addAF

Pathogenic

0.48

BayesDel_noAF

Pathogenic

0.46

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.97

D;D;.

Eigen

Pathogenic

0.69

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Uncertain

0.89

LIST_S2

Pathogenic

1.0

.;D;D

M_CAP

Pathogenic

0.42

MetaRNN

Pathogenic

0.95

D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.4

M;M;.

PrimateAI

Uncertain

0.62

PROVEAN

Pathogenic

-7.1

D;.;.

REVEL

Pathogenic

0.89

Sift

Pathogenic

0.0

D;.;.

Sift4G

Pathogenic

0.0

D;.;.

Polyphen

1.0

D;D;.

Vest4

0.97

MVP

0.98

MPC

0.74

ClinPred

0.98

GERP RS

5.7

Varity_R

0.77

gMVP

0.91

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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