rs188824058

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PM5PP3PP5_Moderate

The NM_003742.4(ABCB11):​c.1460G>T​(p.Arg487Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,544 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. R487H) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

ABCB11
NM_003742.4 missense

Scores

7
10
2

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1

Conservation

PhyloP100: 3.42
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr2-168972025-C-T is described in Lovd as [Pathogenic].
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
Variant 2-168972025-C-A is Pathogenic according to our data. Variant chr2-168972025-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2070502.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ABCB11NM_003742.4 linkc.1460G>T p.Arg487Leu missense_variant Exon 14 of 28 ENST00000650372.1 NP_003733.2 O95342

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ABCB11ENST00000650372.1 linkc.1460G>T p.Arg487Leu missense_variant Exon 14 of 28 NM_003742.4 ENSP00000497931.1 O95342
ABCB11ENST00000439188.1 linkn.8G>T non_coding_transcript_exon_variant Exon 1 of 15 2 ENSP00000416058.1 H7C486

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1460544
Hom.:
0
Cov.:
32
AF XY:
0.00000138
AC XY:
1
AN XY:
726556
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:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Pathogenic:1
Aug 16, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the p.Arg487 amino acid residue in ABCB11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 18395098, 18937870; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. This variant has not been reported in the literature in individuals affected with ABCB11-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 487 of the ABCB11 protein (p.Arg487Leu). -

Progressive familial intrahepatic cholestasis type 2 Uncertain:1
Jan 27, 2025
Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: curation

The p.Arg487Leu variant in ABCB11 has not been previously in the literature in individuals with BSEP deficiency, and has been identified in 0.0001% (1/91028) of South Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs1366346212). Although this variant has been seen in the general population in a heterozygous state, its frequency is low enough to be consistent with a recessive carrier frequency. This variant has also been reported in ClinVar (Variation ID: 2070502) and has been interpreted as likely pathogenic by Invitae. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. Three additional likely pathogenic/pathogenic variants, resulting in a different amino acid change at the same position (p.Arg487Pro, p.Arg487His, p.Arg487Cys), have been reported in association with disease in ClinVar, supporting that a change at this position may not be tolerated (Variation ID: 1070887, 290081, 2201969). In summary, the clinical significance of the p.Arg487Leu variant is uncertain. ACMG/AMP Criteria applied: PM5, PP3, PM2_supporting (Richards 2015). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.52
BayesDel_addAF
Pathogenic
0.39
D
BayesDel_noAF
Pathogenic
0.33
CADD
Pathogenic
34
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.89
D;D
Eigen
Uncertain
0.59
Eigen_PC
Uncertain
0.64
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.96
.;D
M_CAP
Uncertain
0.23
D
MetaRNN
Pathogenic
0.90
D;D
MetaSVM
Pathogenic
0.81
D
MutationAssessor
Benign
1.4
L;L
PrimateAI
Uncertain
0.57
T
PROVEAN
Pathogenic
-5.5
D;.
REVEL
Pathogenic
0.74
Sift
Uncertain
0.0020
D;.
Sift4G
Uncertain
0.0050
D;.
Polyphen
1.0
D;D
Vest4
0.84
MutPred
0.70
Loss of helix (P = 0.2022);Loss of helix (P = 0.2022);
MVP
0.93
MPC
0.69
ClinPred
1.0
D
GERP RS
5.9
Varity_R
0.88
gMVP
0.91

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.56
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.56
Position offset: -17
DS_AL_spliceai
0.22
Position offset: 25

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-169828535; API