rs372685632

Positions:

chr7-87462904-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PM5PP2PP5

The NM_000443.4(ABCB4):c.140G>A(p.Arg47Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000763 in 1,612,680 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R47G) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000078 ( 0 hom. )

Consequence

ABCB4
NM_000443.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:4

Conservation

PhyloP100: 5.60

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:

ABCB4 (HGNC:):

ABCB4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.

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). GenCC has associacion of gene with pancreatitis, low phospholipid associated cholelithiasis, progressive familial intrahepatic cholestasis type 3.

PP5

Variant 7-87462904-C-T is Pathogenic according to our data. Variant chr7-87462904-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 197144.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=4, Pathogenic=1, Likely_pathogenic=3}. Variant chr7-87462904-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABCB4	NM_000443.4 linkuse as main transcript	c.140G>A	p.Arg47Gln	missense_variant	4/28	ENST00000649586.2	NP_000434.1	P21439-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABCB4	ENST00000649586.2 linkuse as main transcript	c.140G>A	p.Arg47Gln	missense_variant	4/28		NM_000443.4	ENSP00000496956.2		P21439-2

Frequencies

GnomAD3 genomes

AF:

0.0000593

AC:

AN:

151696

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000657

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:

0.000103

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000877

AC:

AN:

250894

Hom.:

AF XY:

0.0000590

AC XY:

AN XY:

135592

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.000174

Gnomad ASJ exome

AF:

0.0000995

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000970

Gnomad OTH exome

AF:

0.000491

GnomAD4 exome

AF:

0.0000780

AC:

114

AN:

1460984

Hom.:

Cov.:

AF XY:

0.0000743

AC XY:

AN XY:

726802

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000810

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

AF:

0.0000593

AC:

AN:

151696

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

AN XY:

74050

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.0000657

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000113

Hom.:

Bravo

AF:

0.0000945

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000741

AC:

EpiCase

AF:

0.0000546

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:2Uncertain:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 47 of the ABCB4 protein (p.Arg47Gln). This variant is present in population databases (rs372685632, gnomAD 0.01%). This missense change has been observed in individuals with clinical features of autosomal recessive ABCB4-related conditions (PMID: 20537830, 23533021, 26256905, 28924228, 29761167, 30449124, 31181191, 31538484). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 197144). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on ABCB4 protein function. Studies have shown that this missense change alters ABCB4 gene expression (PMID: 26256905, 31181191). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 15, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 28, 2017	The R47Q variant has been reported previously in patients with PFIC3, LPAC, and IPC who also harbored another ABCB4 gene variant (Davit-Spraul et al., 2010; Poupon et al., 2013; Frider et al., 2015). Expression studies revealed that R47Q is associated with reduced protein levels compared to wild-type, however R47Q was not associated with altered protein localization (Frider et al., 2015). The R47Q variant is observed in 2/11396 (0.02%) alleles from individuals of Latino background, in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The R47Q variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. In summary, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

ABCB4-related disorder

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 28, 2022

The ABCB4 c.140G>A variant is predicted to result in the amino acid substitution p.Arg47Gln. This variant was reported in the compound heterozygous or homozygous states in individuals with low phospholipid associated cholelithiasis (Wendum et al 2012. PubMed ID: 22331132; Frider et al 2015. PubMed ID: 26256905; Poupon et al. 2013. PubMed ID: 23533021; Khabou et al. 2019. PubMed ID: 31181191) and functional studies indicated that it may cause reduced protein levels (Frider et al 2015. PubMed ID: 26256905). This variant is reported in 0.017% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/7-87092220-C-T). Taken together, we classify this variant as likely pathogenic. -

Progressive familial intrahepatic cholestasis

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jan 11, 2024

Variant summary: ABCB4 c.140G>A (p.Arg47Gln) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.8e-05 in 250894 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in ABCB4 causing Familial Intrahepatic Cholestasis (8.8e-05 vs 0.0022), allowing no conclusion about variant significance. c.140G>A has been reported in the literature as homozygous and compound heterozygous genotypes in multiple individuals affected with features of Familial Intrahepatic Cholestasis, namely Low phospholipid-associated cholelithiasis (LPAC)/cholestatic liver disease/Intrahepatic cholestasis of pregnancy (ICP) (example, Poupon_2010, Wendum_2012, Frider_2015, Dixon_2017, Schatz_2018, Huynh_2019, Khabou_2019). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function reporting that the variant does not alter localization but leads to reduced protein levels (Frider_2015). The following publications have been ascertained in the context of this evaluation (PMID: 28924228, 26256905, 31538484, 31181191, 20537830, 29761167, 22331132). ClinVar contains an entry for this variant (Variation ID: 197144). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Progressive familial intrahepatic cholestasis type 3;C2609268:Low phospholipid associated cholelithiasis;C3554241:Cholestasis, intrahepatic, of pregnancy, 3

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 03, 2024

- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 26, 2023

The c.140G>A (p.R47Q) alteration is located in exon 4 (coding exon 3) of the ABCB4 gene. This alteration results from a G to A substitution at nucleotide position 140, causing the arginine (R) at amino acid position 47 to be replaced by a glutamine (Q). Based on data from gnomAD, the A allele has an overall frequency of 0.009% (22/250894) total alleles studied. The highest observed frequency was 0.049% (3/6110) of Other alleles. This variant has been detected as homozygous, heterozygous, and in conjunction with a ABCB4 variant of unknown significance in multiple individuals with clinical features of ABCB4 deficiency (Poupon, 2010; Dixon, 2017; Huynh, 2019; Khabou, 2019; Huynh, 2019; Almes, 2022). This amino acid position is highly conserved in available vertebrate species. A functional study shows the alteration results in reduced expression compared to wild type ABCB4 (Frider, 2015). The in silico prediction for this alteration is inconclusive. Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Low phospholipid associated cholelithiasis

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

The ABCB4 c.140G>A (p.Arg47Gln) variant is a missense variant that has been reported in at least two studies, where it was found in a compound heterozygous state in two individuals with low-phospholipid associated cholestasis syndrome (Wendum et al. 2012; Poupon et al. 2013). Control data are unavailable for this variant, which is reported at a frequency of 0.00009 in the European (non-Finnish) population of the Exome Aggregation Consortium. The evidence for this variant is limited. The p.Arg47Gln variant is thus classified as a variant of unknown significance but suspicious for pathogenicity for ABCB4-related intrahepatic cholestasis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Uncertain

0.081

BayesDel_noAF

Uncertain

0.13

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.75

.;.;D;.;.;.

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.94

.;D;D;D;.;D

M_CAP

Pathogenic

0.41

MetaRNN

Uncertain

0.62

D;D;D;D;D;D

MetaSVM

Uncertain

0.44

MutationAssessor

Benign

0.0

N;N;N;N;N;.

PrimateAI

Uncertain

0.50

PROVEAN

Uncertain

-2.8

.;D;D;D;D;D

REVEL

Pathogenic

0.70

Sift

Uncertain

0.017

.;D;D;D;D;D

Sift4G

Uncertain

0.024

.;D;D;D;D;D

Polyphen

1.0

D;.;D;D;.;.

Vest4

0.41, 0.54, 0.54, 0.41

MVP

0.91

MPC

0.82

ClinPred

0.38

GERP RS

5.5

Varity_R

0.52

gMVP

0.87

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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