rs781266802

chr13-51939095-TCAGAAC-T

Variant summary

Our verdict is Pathogenic. Variant got 15 ACMG points: 15P and 0B. PM1PM2PM4PP3PP5_Very_Strong

The NM_000053.4(ATP7B):c.3649_3654del(p.Val1217_Leu1218del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000186 in 1,614,086 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

ATP7B
NM_000053.4 inframe_deletion

Scores

Not classified

Clinical Significance

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

Conservation

PhyloP100: 9.27

Variant links:

Genes affected

ATP7B (HGNC:870): (ATPase copper transporting beta) This gene is a member of the P-type cation transport ATPase family and encodes a protein with several membrane-spanning domains, an ATPase consensus sequence, a hinge domain, a phosphorylation site, and at least 2 putative copper-binding sites. This protein is a monomer, and functions as a copper-transporting ATPase which exports copper out of the cells, such as the efflux of hepatic copper into the bile. Alternate transcriptional splice variants, encoding different isoforms with distinct cellular localizations, have been characterized. Mutations in this gene have been associated with Wilson disease which is characterized by copper accumulation. [provided by RefSeq, Dec 2019]

ATP7B links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 15 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000053.4

PM2

Very rare variant in population databases, with high coverage;

PM4

Nonframeshift variant in NON repetitive region in NM_000053.4.

PP3

No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

PP5

Variant 13-51939095-TCAGAAC-T is Pathogenic according to our data. Variant chr13-51939095-TCAGAAC-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 189015.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP7B	NM_000053.4 linkuse as main transcript	c.3649_3654del	p.Val1217_Leu1218del	inframe_deletion	17/21	ENST00000242839.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP7B	ENST00000242839.10 linkuse as main transcript	c.3649_3654del	p.Val1217_Leu1218del	inframe_deletion	17/21	1	NM_000053.4	P1	P35670-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000361

AC:

AN:

249600

Hom.:

AF XY:

0.0000443

AC XY:

AN XY:

135410

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.0000353

Gnomad OTH exome

AF:

0.000330

GnomAD4 exome

AF:

0.0000192

AC:

AN:

1461894

Hom.:

AF XY:

0.0000220

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000150

Gnomad4 NFE exome

AF:

0.0000126

Gnomad4 OTH exome

AF:

0.0000993

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152192

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Wilson disease

Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 11, 2019	The ATP7B c.3649_3654delGTTCTG; p.Val1217_Leu1218del variant (rs781266802) also known as 3648del6, is reported in the literature in the compound heterozygous state in multiple individuals affected with Wilson's disease (Ferenci 2005, Folhoffer 2007, Kalinsky 1998, Kemppainen 1997, Loudianos 1998, Petrasek 2007, Thomas 1995, Todorov 2005, Vrabelova 2005, Wright 2009). This variant deletes two amino acid residues leaving the rest of the protein in-frame. This variant is reported in ClinVar (Variation ID: 189015), and is found in the Finnish European population with an allele frequency of 0.014% (3/21,562 alleles) in the Genome Aggregation Database. Based on available information, this variant is considered to be pathogenic. References: Ferenci P et al. Diagnostic value of quantitative hepatic copper determination in patients with Wilson's Disease. Clin Gastroenterol Hepatol. 2005 Aug;3(8):811-8. Folhoffer A et al. Novel mutations of the ATP7B gene among 109 Hungarian patients with Wilson's disease. Eur J Gastroenterol Hepatol. 2007 Feb;19(2):105-11. Kalinsky H et al. Novel ATP7B mutations causing Wilson disease in several Israeli ethnic groups. Hum Mutat. 1998;11(2):145-51. Kemppainen R et al. A homozygous nonsense mutation and a combination of two mutations of the Wilson disease gene in patients with different lysyl oxidase activities in cultured fibroblasts. J Invest Dermatol. 1997 Jan;108(1):35-9. Loudianos G et al. Further delineation of the molecular pathology of Wilson disease in the Mediterranean population. Hum Mutat. 1998;12(2):89-94. Petrasek J et al. Revised King's College score for liver transplantation in adult patients with Wilson's disease. Liver Transpl. 2007 Jan;13(1):55-61. Thomas GR et al. The Wilson disease gene: spectrum of mutations and their consequences. Nat Genet. 1995 Feb;9(2):210-7. Todorov T et al. Spectrum of mutations in the Wilson disease gene (ATP7B) in the Bulgarian population. Clin Genet. 2005 Nov;68(5):474-6. Vrabelova S et al. Mutation analysis of the ATP7B gene and genotype/phenotype correlation in 227 patients with Wilson disease. Mol Genet Metab. 2005 Sep-Oct;86(1-2):277-85. Wright LM et al. Hepatocyte GP73 expression in Wilson disease. J Hepatol. 2009 Sep;51(3):557-64. -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Oct 15, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Aug 23, 2023	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 189015). This variant is also known as 3648del6. This variant has been observed in individual(s) with Wilson disease (PMID: 8980283, 9482578, 17154398, 17272994, 19118915). This variant is present in population databases (rs781266802, gnomAD 0.02%). This variant, c.3649_3654del, results in the deletion of 2 amino acid(s) of the ATP7B protein (p.Val1217_Leu1218del), but otherwise preserves the integrity of the reading frame. -
Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Nov 30, 2023	This variant causes an in-frame deletion of two amino acids (p.Val1217_Leu1218del) in exon 17 of the ATP7B protein. This variant is also known as 3648del6 in the literature. Although functional studies have not been reported, this variant disrupts two conserved amino acids in the Phosphorylation (P) domain (a.a. 1004-1031, 1197-1312) of the ATP7B protein that is involved in the ATP hydrolysis, a highly conserved region that is considered to be important for ATP7B protein function (PMID: 35245129; ClinVar). This variant has been reported in over 15 individuals affected with Wilson disease (PMID: 7626145, 8980283, 9482578, 16207219, 16234011, 17154398, 17272994, 19118915, 19596473, 20082719, 22677543, 25014046, 31708252, 34400371). In several of these individuals, this variant was reported in the compound heterozygous state and homozygous state (PMID: 9482578, 17272994, 19118915). This variant has been identified in 9/249600 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jul 25, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 28, 2022	PP4, PM2, PM3_strong, PM4, PS4_moderate -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	ATP7B: PM3:Strong, PM1, PM2, PM4 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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