rs137853286

chr13-51942395-CG-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000053.4(ATP7B):c.3402del(p.Ala1135GlnfsTer13) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000431 in 1,461,814 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. P1134P) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000043 (0 hom.)
• Consequence: ATP7B NM_000053.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:18 O:1
• Conservation: PhyloP100: -0.448

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 13-51942395-CG-C is Pathogenic according to our data. Variant chr13-51942395-CG-C is described in ClinVar as [Pathogenic]. Clinvar id is 88958.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51942395-CG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP7B	NM_000053.4	c.3402del	p.Ala1135GlnfsTer13	frameshift_variant	15/21	ENST00000242839.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP7B	ENST00000242839.10	c.3402del	p.Ala1135GlnfsTer13	frameshift_variant	15/21	1	NM_000053.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000642 AC: 16 AN: 249374 Hom.: 0 AF XY: 0.0000739 AC XY: 10 AN XY: 135328

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: 0.00

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000431 AC: 63 AN: 1461814 Hom.: 0 Cov.: 32 AF XY: 0.0000399 AC XY: 29 AN XY: 727212

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000531

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000542 Hom.: 0

Bravo AF: 0.0000416

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:18 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Wilson disease Pathogenic:13 Other:1

Pathogenic, criteria provided, single submitter	literature only	Counsyl	Mar 19, 2014	- -
not provided, no classification provided	literature only	ClinVar Staff, National Center for Biotechnology Information (NCBI)	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Sep 01, 2022	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.006%). Frameshift variant is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic with clinical assertions and evidence for the classification (ClinVar ID: VCV000088958 / PMID: 8298641). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 24, 2023	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 25, 2020	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	The ATP7B c.3402delC (p.Ala1135GlnfsTer13) variant results in a frameshift and is predicted to result in premature truncation of the protein. The p.Ala1135GlnfsTer13 variant has been reported in seven studies in which it is found in a total of 80 patients with Wilson disease, including in 24 in a homozygous state, in 48 in a compound heterozygous state and in eight in a heterozygous state (Tanzi et al. 1993; Deguti et al. 2004; Gromadzka et al. 2005; Kucinskas et al. 2008; Machado et al. 2008; Bem et al. 2013; Paradisi et al. 2014). Control data are unavailable for this variant, which is reported at a frequency of 0.00019 in the European (non-Finnish) population of the Exome Aggregation Consortium. Based on the evidence and potential impact of frameshift variants, the p.Ala1135GlnfsTer13 variant is classified as pathogenic for Wilson disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 28, 2020	Variant summary: ATP7B c.3402delC (p.Ala1135GlnfsX13) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory. The variant allele was found at a frequency of 6.4e-05 in 249374 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in ATP7B causing Wilson Disease (6.4e-05 vs 0.0054), allowing no conclusion about variant significance. c.3402delC has been reported in the literature in multiple individuals affected with Wilson Disease (Balashova_2019, Naorniakowska 2016, Gromadzka 2005, Caca 2001, Tanzi 1993). These data indicate that the variant is very likely to be associated with disease. At least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated subcellular mislocalization (Huster_2003). Six ClinVar submitters (evaluation after 2014) cite the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 29, 2023	This sequence change creates a premature translational stop signal (p.Ala1135Glnfs*13) in the ATP7B gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ATP7B are known to be pathogenic (PMID: 10441329, 16283883). This variant is present in population databases (rs137853281, gnomAD 0.01%). This premature translational stop signal has been observed in individual(s) with Wilson disease (PMID: 8298641, 15024742, 16283883, 25497208). ClinVar contains an entry for this variant (Variation ID: 88958). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 13, 2023	This variant deletes 1 nucleotide in exon 15 of the ATP7B gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. Functional studies have shown that this variant disrupts intracellular localization (PMID: 12557139). This variant has been reported in the homozygous state or with a co-occurring pathogenic ATP7B variant in many individuals affected with Wilson disease and has been described as a common mutation in German, Brazilian, Polish, Venezuelan, and Russian populations (PMID: 8298641, 11690702, 15024742, 16283883, 25497208, 31708252, 34400371, 35169583). This variant has been identified in 17/280726 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Loss of ATP7B function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Centre for Mendelian Genomics, University Medical Centre Ljubljana	Sep 23, 2019	This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PS1. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 11, 2020	The p.Ala1135GlnfsX13 variant in ATP7B has been reported in many individuals with Wilson disease, including >20 homozygotes and >20 compound heterozygotes (Bem 2013, Caca 2001, Deguti2004, Firneisz 2002, Gromadzka 2005, Haas 1999, Kluska 2019, Kucisnskas 2008, Margarit 2005, Paradisi 2015, Tanzi 1993, Waldenstrom 1996). It has also been identified in 0.01% (17/128568) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org), which is a low enough freuqncy to be consistent with a recessive Wilson disease allele. This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 1135 and leads to a premature termination codon 13 amino acids downstream. This alteration is then predicted to lead to a truncated or absent protein. Loss of function of ATP7B is an established disease mechanism for Wilson disease. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Wilson disease. ACMG/AMP criteria applied: PVS1, PM3_VeryStrong, PM2. -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 25, 2019	The ATP7B c.3402delC; p.Ala1135fs variant (rs137853281), also published as 3400delC or 3403delC, is reported in the literature in individuals with a clinical diagnosis of Wilson disease (Deguti 2004, Duc 1998, Firneisz 2002, Margarit 2005, Thomas 1995). This variant has been reported in the homozygous state and has also been reported in affected individuals carrying a second pathogenic variant (Deguti 2004). The p.Ala1135fs variant is described in the ClinVar database (Variation ID: 88958) and is observed in the Genome Aggregation Database with a low frequency of 0.01% (17/128568 alleles) in the non-Finnish European population. This variant causes a frameshift by deleting a single nucleotide, so it is predicted to result in a truncated protein or mRNA subject to nonsense-mediated decay. Based on available information, this variant is considered to be pathogenic. References: Deguti MM et al. Wilson disease: novel mutations in the ATP7B gene and clinical correlation in Brazilian patients. Hum Mutat. 2004 23(4):398. Duc HH et al. His1069Gln and six novel Wilson disease mutations: analysis of relevance for early diagnosis and phenotype. Eur J Hum Genet. 1998 Nov-Dec;6(6):616-23. Firneisz G et al. Common mutations of ATP7B in Wilson disease patients from Hungary. Am J Med Genet. 2002 Feb 15;108(1):23-8. Margarit E et al. Mutation analysis of Wilson disease in the Spanish population -- identification of a prevalent substitution and eight novel mutations in the ATP7B gene. Clin Genet. 2005 Jul;68(1):61-8. Thomas GR et al. The Wilson disease gene: spectrum of mutations and their consequences. Nat Genet. 1995 Feb;9(2):210-7. -

not provided Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 20, 2023	Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25497208, 31589614, 34400371, 32270360, 32043565, 11690702, 15967699, 23982005, 20082719, 23789284, 8533760, 11857545, 26819605, 12557139, 31708252, 32067425, 8298641, 18855987, 33159804, 15024742) -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 08, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	ATP7B: PVS1, PM2, PM3, PP4 -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Computational scores

Source: dbNSFP v4.3

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

LitVar

Other links and lift over

dbSNP: rs137853281; hg19: chr13-52516531;