7-87444965-GA-GAA

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), Orphanet, ClinGen
gallbladder disease 1
Inheritance: SD, AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)
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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000443.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ABCB4	NM_000443.4	MANE Select	c.1015dupT	p.Ser339PhefsTer17	frameshift	Exon 10 of 28	NP_000434.1	P21439-2
ABCB4	NM_018849.3		c.1015dupT	p.Ser339PhefsTer17	frameshift	Exon 10 of 28	NP_061337.1	P21439-1
ABCB4	NM_018850.3		c.1015dupT	p.Ser339PhefsTer17	frameshift	Exon 10 of 27	NP_061338.1	P21439-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ABCB4	ENST00000649586.2	MANE Select	c.1015dupT	p.Ser339PhefsTer17	frameshift	Exon 10 of 28	ENSP00000496956.2	P21439-2
ABCB4	ENST00000265723.8	TSL:1	c.1015dupT	p.Ser339PhefsTer17	frameshift	Exon 10 of 28	ENSP00000265723.4	P21439-1
ABCB4	ENST00000359206.8	TSL:1	c.1015dupT	p.Ser339PhefsTer17	frameshift	Exon 10 of 28	ENSP00000352135.3	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), 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

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Progressive familial intrahepatic cholestasis type 3 (2)

ABCB4-related disorder (1)

Cholestasis, intrahepatic, of pregnancy, 3 (1)

Computational scores

Source: dbNSFP v4.9

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

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over