rs141677867

Variant summary

Our verdict is Pathogenic. Variant got 19 ACMG points: 19P and 0B. PM1PM2PM5PP2PP3_StrongPP5_Very_Strong

The NM_000443.4(ABCB4):c.2177C>T(p.Pro726Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,613,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/20 in silico tools predict a damaging 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. P726T) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

ABCB4
NM_000443.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: 9.28

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 19 ACMG points.

PM1

In a transmembrane_region Helical (size 20) in uniprot entity MDR3_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_000443.4

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 where missense usually causes diseases, ABCB4

PP3

MetaRNN computational evidence supports a deleterious effect, 0.979

PP5

Variant 7-87423940-G-A is Pathogenic according to our data. Variant chr7-87423940-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 194709.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-87423940-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ABCB4	NM_000443.4 linkuse as main transcript	c.2177C>T	p.Pro726Leu	missense_variant	17/28	ENST00000649586.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ABCB4	ENST00000649586.2 linkuse as main transcript	c.2177C>T	p.Pro726Leu	missense_variant	17/28		NM_000443.4	P1	P21439-2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152092

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251176

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135728

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000137

AC:

AN:

1461802

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

727214

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000144

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152092

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74286

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.0000278

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 07, 2024	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 726 of the ABCB4 protein (p.Pro726Leu). This variant is present in population databases (rs141677867, gnomAD 0.003%). This missense change has been observed in individuals with low-phospholipid-associated cholelithiasis syndrome and/or progressive familial intrahepatic cholestasis type 3 (PMID: 20422496, 23533021, 26474921, 28733223, 29761167). ClinVar contains an entry for this variant (Variation ID: 194709). 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. Experimental studies have shown that this missense change affects ABCB4 function (PMID: 26474921, 28012258). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2023	ABCB4: PM2, PM5, PS3:Moderate, PP4, PS4:Supporting -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 06, 2023	Has been observed as a single heterozygous variant, as homozygous variant, or with a second ABCB4 variant in patients with abnormal liver tests, cholelithias, cholestasis and/or cholangitis (Davit- Spraul et al., 2010; Poupon et al., 2013; Lin et al., 2014; Delaunay et al., 2015; Elderman et al., 2015); Published functional studies demonstrate a damaging effect as the P726L variant abolishes phosphatidylchoine secretion (Delaunay et a;., 2015; Delaunay et al., 2017); Not observed at significant frequency in large population cohorts (gnomAD); 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: 26474921, 28012258, 20422496, 28757171, 23533021, 25612754, 31589614, 33842647, 32893960, 34961929, 32917322, 35894240, 36569137) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 03, 2017	- -

Progressive familial intrahepatic cholestasis type 3

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Rolfs Rare Disease Consulting, Rolfs Consulting Und Verwaltungs GmbH	Jan 01, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	3billion	Jan 03, 2022	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (PMID: 23533021 VCV000194709, , PS1_S). A different missense change at the same codon has been reported to be associated with ABCB4 related disorder (PMID:17726488, PM5_P). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.905, 3CNET: 0.897, PP3_P). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000008, PM2_M). Therefore, this variant is classified as likely pathogenic according to the recommendation of ACMG/AMP guideline. -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 25, 2022

- -

ABCB4-related condition

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 01, 2024

The ABCB4 c.2177C>T variant is predicted to result in the amino acid substitution p.Pro726Leu. This variant in the presence and absence of a second causative variant has been reported in patients with progressive familial intrahepatic cholestasis type 3 (PFIC3) or Low-Phospholipid-Associated Cholelithiasis (see for example Poupon et al. 2013. PubMed ID: 23533021; Delaunay et al. 2016. PubMed ID: 26474921; Elderman et al. 2015. PubMed ID: 25612754). Functional studies demonstrated that this variant resulted in near absence of phosphatidylcholine secretion (Delaunay et al. 2016. PubMed ID: 26474921). Additionally, a different substitution of the same amino acid (p.Pro726Thr) has been well documented as causative for PFIC3 (Degiorgio et al. 2007. PubMed ID: 17726488). This variant is reported in 0.0029% of alleles in individuals of Latino descent in gnomAD. In ClinVar, this variant is interpreted as likely pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/194709/). This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.86

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.43

Cadd

Pathogenic

Dann

Pathogenic

1.0

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Uncertain

0.96

M_CAP

Pathogenic

0.39

MetaRNN

Pathogenic

0.98

D;D;D;D;D

MetaSVM

Pathogenic

0.93

MutationAssessor

Pathogenic

4.0

H;H;H;H;H

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Uncertain

0.67

Polyphen

1.0

D;.;D;D;.

Vest4

0.93, 0.90, 0.90, 0.93

MutPred

0.84

Gain of stability (P = 0.1008);Gain of stability (P = 0.1008);Gain of stability (P = 0.1008);Gain of stability (P = 0.1008);Gain of stability (P = 0.1008);

MVP

0.97

MPC

0.97

ClinPred

1.0

GERP RS

6.1

Varity_R

0.93

gMVP

0.89

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