NM_000443.4:c.1015dupT

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1PP5

The NM_000443.4(ABCB4):c.1015dupT(p.Ser339PhefsTer17) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00119 in 1,553,300 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0013 ( 0 hom. )

Consequence

ABCB4
NM_000443.4 frameshift

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:5U:1

Conservation

PhyloP100: 2.53

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_pathogenic. The variant received 9 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 7-87444965-G-GA is Pathogenic according to our data. Variant chr7-87444965-G-GA is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 812984.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ABCB4	NM_000443.4 link	c.1015dupT	p.Ser339PhefsTer17	frameshift_variant	Exon 10 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.1015dupT	p.Ser339PhefsTer17	frameshift_variant	Exon 10 of 28		NM_000443.4	ENSP00000496956.2		P21439-2

Frequencies

GnomAD3 genomes

AF:

0.0000335

AC:

AN:

149280

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000246

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000666

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000212

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000297

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000853

AC:

178

AN:

208602

AF XY:

0.000802

show subpopulations

Gnomad AFR exome

AF:

0.000507

Gnomad AMR exome

AF:

0.000802

Gnomad ASJ exome

AF:

0.000568

Gnomad EAS exome

AF:

0.000192

Gnomad FIN exome

AF:

0.00212

Gnomad NFE exome

AF:

0.000832

Gnomad OTH exome

AF:

0.000387

GnomAD4 exome

AF:

0.00131

AC:

1838

AN:

1403916

Hom.:

Cov.:

AF XY:

0.00118

AC XY:

828

AN XY:

698796

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00125

AC:

AN:

32032

American (AMR)

AF:

0.000708

AC:

AN:

42394

Ashkenazi Jewish (ASJ)

AF:

0.000921

AC:

AN:

24970

East Asian (EAS)

AF:

0.000447

AC:

AN:

38032

South Asian (SAS)

AF:

0.000796

AC:

AN:

82918

European-Finnish (FIN)

AF:

0.000890

AC:

AN:

41594

Middle Eastern (MID)

AF:

0.000890

AC:

AN:

5618

European-Non Finnish (NFE)

AF:

0.00144

AC:

1558

AN:

1078258

Other (OTH)

AF:

0.00107

AC:

AN:

58100

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.243

Heterozygous variant carriers

308

617

925

1234

1542

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

156

234

312

390

<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:

0.0000335

AC:

AN:

149384

Hom.:

Cov.:

AF XY:

0.0000549

AC XY:

AN XY:

72804

show subpopulations

African (AFR)

AF:

0.0000245

AC:

AN:

40750

American (AMR)

AF:

0.0000666

AC:

AN:

15024

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3436

East Asian (EAS)

AF:

0.00

AC:

AN:

5116

South Asian (SAS)

AF:

0.000212

AC:

AN:

4718

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9770

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000297

AC:

AN:

67300

Other (OTH)

AF:

0.00

AC:

AN:

2072

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00382

Hom.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:5Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Progressive familial intrahepatic cholestasis type 3

Pathogenic:2

Apr 20, 2022

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG classification criteria: PVS1 very strong, PS4 moderated, PM2 moderated -

May 06, 2021

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with intrahepatic cholestasis of pregnancy 3 (ICP-3) (MIM#614972), gallbladder disease 1 (low phospholipid-associated cholelithiasis (LPAC)) (MIM# 600803) and progressive familial intrahepatic cholestasis 3 (PFIC) (MIM#602347). (I) 0108 - This gene is associated with both recessive and dominant disease. PFIC is inherited in a recessive manner, whereas ICP-3 and LPAC can be either dominant or recessive. Biallelic variants typically demonstrate less residual protein activity, resulting in earlier onset of the condition with a more severe phenotype (OMIM, PMID: 24806754, PMID: 32376413). (I) 0112 - The condition associated with this gene has incomplete penetrance. A single case of an asymptomatic sibling homozygous for a null variant has been reported (PMID: 32376413). (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0251 - This variant is heterozygous. (I) 0302 - Variant is present in gnomAD (v3) <0.001 for a dominant condition (5 heterozygotes, 0 homozygotes). (SP) 0701 - Other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (ClinVar). (SP) 0801 - This variant has strong previous evidence of pathogenicity in three unrelated heterozygous individuals with low phospholipid-associated cholelithiasis and three additional heterozygous individuals with intrahepatic cholestasis of pregnancy (PMID: 23533021, 32581362, 33554096). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -

not provided

Pathogenic:1Uncertain:1

Dec 30, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change creates a premature translational stop signal (p.Ser339Phefs*17) in the ABCB4 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ABCB4 are known to be pathogenic (PMID: 17726488, 25755532). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This premature translational stop signal has been observed in individual(s) with ABCB4-related conditions (PMID: 32581362, 32893960). ClinVar contains an entry for this variant (Variation ID: 812984). For these reasons, this variant has been classified as Pathogenic. -

Sep 07, 2021

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

ABCB4-related disorder

Pathogenic:1

Aug 28, 2024

PreventionGenetics, part of Exact Sciences

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

The ABCB4 c.1015dupT variant is predicted to result in a frameshift and premature protein termination (p.Ser339Phefs*17). This variant has been reported in the heterozygous state in multiple individuals with low phospholipid associated cholelithiasis (Rosmorduc et al. 2003. PubMed ID: 12891548; Poupon et al. 2013. PubMed ID: 23533021; Turro et al. 2020. PubMed ID: 32581362; Table S1, de Vries et al. 2020. PubMed ID: 32893960). This variant is reported in 0.17% of alleles in individuals of European (Finnish) descent in gnomAD; however, this variant failed to pass quality control filters in the gnomAD data. Frameshift variants in ABCB4 are expected to be pathogenic. Given the evidence, we interpret this variant as pathogenic. -

Cholestasis, intrahepatic, of pregnancy, 3

Pathogenic:1

NIHR Bioresource Rare Diseases, University of Cambridge

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.5

Mutation Taster

=0/200

disease causing (ClinVar)

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over