rs142794414

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PP2BP4_StrongBS1_Supporting

The NM_000443.4(ABCB4):c.101C>T(p.Thr34Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000323 in 1,608,124 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. 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. T34K) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00023 ( 0 hom. )

Consequence

ABCB4
NM_000443.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8B:1

Conservation

PhyloP100: -0.199

Publications

11 publications found

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 Gene-Disease associations (from GenCC):

progressive familial intrahepatic cholestasis type 3
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet
gallbladder disease 1
Inheritance: SD, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
pancreatitis
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ABCB4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

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 gallbladder disease 1, progressive familial intrahepatic cholestasis type 3, pancreatitis.

BP4

Computational evidence support a benign effect (MetaRNN=0.0068332255).

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00123 (187/152030) while in subpopulation AFR AF = 0.00417 (173/41448). AF 95% confidence interval is 0.00367. There are 0 homozygotes in GnomAd4. There are 95 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCB4	NM_000443.4 link	c.101C>T	p.Thr34Met	missense_variant	Exon 3 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.101C>T	p.Thr34Met	missense_variant	Exon 3 of 28		NM_000443.4	ENSP00000496956.2		P21439-2

Frequencies

GnomAD3 genomes

AF:

0.00121

AC:

184

AN:

151912

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00411

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.000957

GnomAD2 exomes

AF:

0.000483

AC:

121

AN:

250774

AF XY:

0.000325

show subpopulations

Gnomad AFR exome

AF:

0.00573

Gnomad AMR exome

AF:

0.000551

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000529

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.000228

AC:

332

AN:

1456094

Hom.:

Cov.:

AF XY:

0.000232

AC XY:

168

AN XY:

724850

show subpopulations

African (AFR)

AF:

0.00462

AC:

154

AN:

33356

American (AMR)

AF:

0.000605

AC:

AN:

44658

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26086

East Asian (EAS)

AF:

0.00

AC:

AN:

39586

South Asian (SAS)

AF:

0.0000465

AC:

AN:

86030

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53402

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5750

European-Non Finnish (NFE)

AF:

0.0000985

AC:

109

AN:

1107038

Other (OTH)

AF:

0.000532

AC:

AN:

60188

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.415

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00123

AC:

187

AN:

152030

Hom.:

Cov.:

AF XY:

0.00128

AC XY:

AN XY:

74314

show subpopulations

African (AFR)

AF:

0.00417

AC:

173

AN:

41448

American (AMR)

AF:

0.000393

AC:

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.000415

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10548

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

67988

Other (OTH)

AF:

0.000947

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000552

Hom.:

Bravo

AF:

0.00141

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00454

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000610

AC:

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.000109

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:5

Feb 24, 2023

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BS1 -

Dec 21, 2017

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 15, 2020

Revvity Omics, Revvity

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jul 06, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 34 of the ABCB4 protein (p.Thr34Met). This variant is present in population databases (rs142794414, gnomAD 0.5%). This missense change has been observed in individual(s) with clinical features of progressive familial intrahepatic cholestasis or low phospholipid associated cholelithiasis syndrome (PMID: 22331132, 24723470, 28355206). ClinVar contains an entry for this variant (Variation ID: 196273). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The methionine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. Experimental studies have shown that this missense change affects ABCB4 function (PMID: 24723470). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

ABCB4-related disorder

Uncertain:1

Mar 07, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The ABCB4 c.101C>T variant is predicted to result in the amino acid substitution p.Thr34Met. This variant has been reported in the heterozygous state in an individual with low phospholipid-associated cholelithiasis (Wendum et al. 2012. PubMed ID: 22331132, Table 2, Patient 3). In vitro functional studies indicate that this variant does not impact protein stability, expression, and apical plasma membrane localization, but decreases ABCB4-mediated phosphatidylcholine secretion activity and impairs ABCB4 phosphorylation (Gautherot et al. 2014. PubMed ID: 24723470). This variant is reported in 0.48% of alleles in individuals of African descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Cholestasis, intrahepatic, of pregnancy, 3

Uncertain:1

Apr 04, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

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

Uncertain:1

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Progressive familial intrahepatic cholestasis type 1

Benign:1

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.48

CADD

Benign

0.92

(source)

DANN

Benign

0.69

DEOGEN2

Benign

0.32

.;.;T;.;.;.

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.011

LIST_S2

Benign

0.38

.;T;T;T;.;T

MetaRNN

Benign

0.0068

T;T;T;T;T;T

MetaSVM

Benign

-0.77

MutationAssessor

Benign

0.0

N;N;N;N;N;.

PhyloP100

-0.20

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.060

.;N;N;N;N;N

REVEL

Pathogenic

0.69

Sift

Benign

0.19

.;T;T;T;T;T

Sift4G

Benign

0.12

.;T;T;T;T;T

Polyphen

0.0050

B;.;B;B;.;.

Vest4

0.17, 0.19, 0.19, 0.17

MVP

0.38

MPC

0.29

ClinPred

0.0034

GERP RS

-8.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.017

gMVP

0.24

Mutation Taster

=4/96

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over