Variant 13-51960253-CAGCATAT-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_000053.4(ATP7B):c.2009_2015del(p.Tyr670Ter) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000273 in 1,613,844 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

ATP7B
NM_000053.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:14

Conservation

PhyloP100: 9.26

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 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 13-51960253-CAGCATAT-C is Pathogenic according to our data. Variant chr13-51960253-CAGCATAT-C is described in ClinVar as [Pathogenic]. Clinvar id is 188862.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.2009_2015del	p.Tyr670Ter	frameshift_variant	7/21	ENST00000242839.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP7B	ENST00000242839.10 linkuse as main transcript	c.2009_2015del	p.Tyr670Ter	frameshift_variant	7/21	1	NM_000053.4	P1	P35670-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152196

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:

0.0000241

AC:

AN:

249204

Hom.:

AF XY:

0.0000370

AC XY:

AN XY:

135188

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:

0.00

Gnomad NFE exome

AF:

0.0000531

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000287

AC:

AN:

1461648

Hom.:

AF XY:

0.0000234

AC XY:

AN XY:

727134

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:

0.00

Gnomad4 NFE exome

AF:

0.0000378

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152196

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74348

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:

0.0000453

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Wilson disease

Pathogenic:12

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 20, 2022	- -
Pathogenic, no assertion criteria provided	research	deCODE genetics, Amgen	Jul 21, 2023	The variant NM_000053.4:c.2009_2015del (chr13:51960253) in ATP7B was detected in 619 heterozygotes and 4 homozygotes out of 58K WGS Icelanders (MAF= 0,541%). Following imputation in a set of 166K Icelanders (1,782 imputed heterozygotes and 7 imputed homozygotes) we observed an association with disorders of copper metabolism (ICD10 code: E830) under a recessive model using 26 cases and 302580 controls (OR= 244.2, P= 1.9e-18). This variant has been reported in ClinVar previously as pathogenic. Based on ACMG criteria (PVS1, PS4, PP5) this variant classifies as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 04, 2024	This sequence change creates a premature translational stop signal (p.Tyr670*) 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 (rs779904655, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with Wilson disease (PMID: 7726170). It has also been observed to segregate with disease in related individuals. This variant is also known as 2010del7. ClinVar contains an entry for this variant (Variation ID: 188862). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 23, 2022	The ATP7B c.2009_2015del; p.Tyr670Ter variant (rs779904655), also known as 1950-1956 deletion, has been described in individuals and families affected with Wilson disease (Bull 1993, Thomas 1995). The variant is reported in ClinVar (Variation ID: 188862), and is observed in the general population at an overall frequency of 0.0024% (6/249204 alleles) in the Genome Aggregation Database. This variant deletes seven nucleotides resulting in an immediate stop codon, 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 Bull PC et al. The Wilson disease gene is a putative copper transporting P-type ATPase similar to the Menkes gene. Nat Genet. 1993 Dec;5(4):327-37. PMID: 8298639. Thomas GR et al. Wilson disease in Iceland: a clinical and genetic study. Am J Hum Genet. 1995 May;56(5):1140-6. PMID: 7726170. -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 22, 2024	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Aug 27, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Feb 03, 2017	Variant summary: The ATP7B c.2009_2015delATATGCT (p.Tyr670Terfs) variant results in a premature termination codon, predicted to cause a truncated or absent ATP7B 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 (e.g. c.3402delC, p.Ala1135fs). One in silico tool predicts a damaging outcome for this variant. This variant was found in 2/120512 control chromosomes at a frequency of 0.0000166, which does not exceed the estimated maximal expected allele frequency of a pathogenic ATP7B variant (0.0054006). The variant has been reported in affected individuals in the literature in both the homozygous and compound heterozygous state. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely pathogenic/pathogenic. Taken together, this variant is classified as pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Counsyl	Feb 23, 2018	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 11, 2020	The p.Tyr670X variant in ATP7B has been reported in at least 2 homozygous individuals with Wilson disease and segregated with disease in 4 affected individuals from 2 families (Bull 1993, Thomas 1995, Curtis 1999). It has also been identified in 0.005% (6/112946) of chromosomes in Europeans by gnomAD (http://gnomad.broadinstitute.org). This variant has also been reported in ClinVar (Variation ID 188862). This deletion leads to a premature termination codon at position 670 , which is predicted to lead to a truncated or absent protein. Loss of function of the ATP7B gene is an established disease mechanism in autosomal recessive Wilson Disease. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Wilson disease. ACMG/AMP criteria applied: PVS1, PP1_Strong, PM2, PM3, PP4. -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 01, 1995	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Aug 15, 2023	This variant deletes 7 nucleotides in exon 7 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. This variant is also known as 1950-1956 deletion, 2010del7, or 2007del7 in the literature. This variant has been observed in the homozygous state in individuals affected with autosomal recessive Wilson disease (PMID: 8298639, 7726170, 10502777), indicating that this variant contributes to disease. This variant has been identified in 6/249204 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	Color Diagnostics, LLC DBA Color Health	Feb 15, 2023	This variant deletes 7 nucleotides in exon 7 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. This variant is also known as 1950-1956 deletion, 2010del7, or 2007del7 in the literature. This variant has been observed in the homozygous state in individuals affected with autosomal recessive Wilson disease (PMID: 8298639, 7726170, 10502777), indicating that this variant contributes to disease. This variant has been identified in 6/249204 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. -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	ATP7B: PVS1, PP1:Strong, PM2, PM3 -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 09, 2022	Nonsense 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: 7726170, 8298639, 10502777) -

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

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