rs72552778

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP2PP3PP5_Very_Strong

The NM_000443.4(ABCB4):c.959C>T(p.Ser320Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000174 in 1,613,618 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 (★★).

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00017 ( 0 hom. )

Consequence

ABCB4
NM_000443.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14U:1

Conservation

PhyloP100: 3.28

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 14 ACMG points.

PM1

In a helix (size 52) in uniprot entity MDR3_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_000443.4

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the ABCB4 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 32 curated pathogenic missense variants (we use a threshold of 10). The gene has 6 curated benign missense variants. Gene score misZ: 1.9749 (below the threshold of 3.09). Trascript score misZ: 3.5425 (above the threshold of 3.09). GenCC associations: The gene is linked to pancreatitis, low phospholipid associated cholelithiasis, progressive familial intrahepatic cholestasis type 3.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.795

PP5

Variant 7-87447080-G-A is Pathogenic according to our data. Variant chr7-87447080-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 13690.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-87447080-G-A is described in Lovd as [Pathogenic]. Variant chr7-87447080-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCB4	NM_000443.4 link	c.959C>T	p.Ser320Phe	missense_variant	Exon 9 of 28	ENST00000649586.2	NP_000434.1	P21439-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ABCB4	ENST00000649586.2 link	c.959C>T	p.Ser320Phe	missense_variant	Exon 9 of 28		NM_000443.4	ENSP00000496956.2		P21439-2

Frequencies

GnomAD3 genomes

AF:

0.000171

AC:

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.000309

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000155

AC:

AN:

251176

Hom.:

AF XY:

0.000162

AC XY:

AN XY:

135746

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000174

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:

0.000291

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000174

AC:

254

AN:

1461466

Hom.:

Cov.:

AF XY:

0.000164

AC XY:

119

AN XY:

727062

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000134

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000214

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.000171

AC:

AN:

152152

Hom.:

Cov.:

AF XY:

0.000229

AC XY:

AN XY:

74324

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000309

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000232

Hom.:

Bravo

AF:

0.000155

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000115

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:6

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 08, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 320 of the ABCB4 protein (p.Ser320Phe). This variant is present in population databases (rs72552778, gnomAD 0.03%). This missense change has been observed in individuals with clinical features of autosomal recessive progressive familial intrahepatic cholestasis type 3 (PMID: 11313316, 32893960). ClinVar contains an entry for this variant (Variation ID: 13690). 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: 24806754). For these reasons, this variant has been classified as Pathogenic. -

Aug 24, 2018

Eurofins Ntd Llc (ga)

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 01, 2021

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 15, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

One in vitro study showed decreased transport activity, while another showed reduced protein expression but normal protein function (PMID: 26153658, 24381502); 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: 19490418, 17562004, 26699824, 23533021, 24381502, 22331132, 11313316, 19840255, 17786139, 19584064, 15077010, 16890614, 17726488, 21119540, 26324191, 28776642, 29761167, 24806754, 28733223, 30487145, 31538484, 32793533, 32581362, 35288833, 37822304, 34376370, 33258288, 36330364, 33390354, 32893960, 32650689, 26153658) -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Low phospholipid associated cholelithiasis

Pathogenic:3

Oct 01, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

May 04, 2022

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Across a selection of the available literature, the ABCB4 c.959C>T (p.Ser320Phe) missense variant has been identified in a homozygous state in four patients with intrahepatic cholestasis of pregnancy, in a homozygous state in one patient with progressive familial intrahepatic cholestasis type 3, in a homozygous state in one patient with low phospholipid associated cholelithiasis, and in a compound heterozygotes state in seven patients with progressive familial intrahepatic cholestasis type 3 (Rosmorduc et al. 2001; Rosmorduc et al. 2003; Pauli-Magnus et al. 2004; Keitel et al. 2006; Degiorgio et al. 2007; Colombo et al. 2011; Oliveira et al. 2016). The p.Ser320Phe variant was absent from 630 controls and is reported at a frequency of 0.00020 in the European (non-Finnish) population of the Exome Aggregation Consortium. Transfection of the p.Ser320Phe variant into HEK293T and MDCK-II cells showed that the variant protein had similar activity as compared to wild type, however the expression levels were slightly reduced (Kim et al. 2013; Andress et al. 2014; Gordo-Gilart et al. 2016). Based on the evidence, the p.Ser320Phe variant is classified as pathogenic for ABCB4-related intrahepatic cholestasis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Cholestasis, intrahepatic, of pregnancy, 3

Pathogenic:2

Oct 01, 2009

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

NIHR Bioresource Rare Diseases, University of Cambridge

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

ABCB4-related disorder

Pathogenic:1

Mar 05, 2024

PreventionGenetics, part of Exact Sciences

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The ABCB4 c.959C>T variant is predicted to result in the amino acid substitution p.Ser320Phe. This variant has been reported in the homozygous or compound heterozygous state in several individuals with cholestasis phenotypes (see for example, Rosmorduc et al. 2001. PubMed ID: 11313316; Keitel et al. 2006. PubMed ID: 16890614; Degiorgio et al. 2007 PubMed ID: 17726488). In vitro functional assessment has been inconclusive (Kim et al. 2013. PubMed ID: 24381502; Andress et al. 2014. PubMed ID: 24806754; Gordo-Gilart et al. 2015. PubMed ID: 26153658). This variant is reported in 0.029% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as likely pathogenic. -

Progressive familial intrahepatic cholestasis

Pathogenic:1

Mar 02, 2023

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

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: ABCB4 c.959C>T (p.Ser320Phe) results in a non-conservative amino acid change located in the ABC transporter type 1, transmembrane domain (IPR011527) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 251176 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in ABCB4 causing Familial Intrahepatic Cholestasis (0.00016 vs 0.0022), allowing no conclusion about variant significance. c.959C>T has been reported in the literature in multiple individuals affected with Familial Intrahepatic Cholestasis (example: Rosmmorduc_2001 and de Vries_2020). These data indicate that the variant is very likely to be associated with disease. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

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

Pathogenic:1

May 22, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Progressive familial intrahepatic cholestasis type 3

Uncertain:1

Aug 22, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: flagged submission

Collection Method: clinical testing

The Ser320Phe variant in ABCB4 has been reported in 9 heterozygous, 6 homozygous, and 4 compound heterozygous individuals with cholestatic liver disease (Andress 2014, Poupon 2013, Wendum 2012, Bacq 2009, Degiorgio 2007, Colombo 2011, Rosmorduc 2001, Pauli-Magnus 2004, Zimmer 2009, Keitel 2006). This variant has been identified in 1/8600 of European American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs72552778). Computational analyses (biochemical amino acid properties, conservation and PolyPhen2) do not provide strong support for or against an impact to the protein. In vitro assays suggest the Ser320Phe variant may affect protein function (Andress 2014, Kim 2013); however these types of assays may not accurately represent biological function. In summary, while there is some suspicion for a pathogenic role, the clinical significance of the Ser320Phe variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.69

BayesDel_addAF

Pathogenic

0.20

BayesDel_noAF

Pathogenic

0.36

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.74

.;.;D;.;.

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.97

.;D;D;D;.

M_CAP

Pathogenic

0.58

MetaRNN

Pathogenic

0.80

D;D;D;D;D

MetaSVM

Pathogenic

0.85

MutationAssessor

Uncertain

2.5

M;M;M;M;M

PrimateAI

Uncertain

0.58

PROVEAN

Uncertain

-3.7

.;D;D;D;D

REVEL

Pathogenic

0.83

Sift

Uncertain

0.0010

.;D;D;D;D

Sift4G

Uncertain

0.0060

.;D;D;D;D

Polyphen

0.95

P;.;P;P;.

Vest4

0.83, 0.82, 0.84, 0.84

MVP

0.95

MPC

0.93

ClinPred

0.35

GERP RS

5.7

Varity_R

0.88

gMVP

0.97

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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