rs753962912

Positions:

Variant summary

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

The NM_000053.4(ATP7B):c.1745_1746del(p.Ile582ArgfsTer25) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000223 in 1,614,124 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. I582I) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000021 ( 0 hom. )

Consequence

ATP7B
NM_000053.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 8.89

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:

Genome browser will be placed here

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 13-51964994-CTA-C is Pathogenic according to our data. Variant chr13-51964994-CTA-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 189112.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.1745_1746del	p.Ile582ArgfsTer25	frameshift_variant	5/21	ENST00000242839.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP7B	ENST00000242839.10 linkuse as main transcript	c.1745_1746del	p.Ile582ArgfsTer25	frameshift_variant	5/21	1	NM_000053.4	P1	P35670-1

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152116

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:

0.0000882

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000160

AC:

AN:

249568

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135394

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:

0.0000353

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000205

AC:

AN:

1461890

Hom.:

AF XY:

0.0000179

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

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:

0.0000252

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152234

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74424

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:

0.0000882

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000377

Hom.:

Bravo

AF:

0.0000340

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Wilson disease

Pathogenic:8

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	May 26, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jul 16, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Nov 02, 2023	This variant deletes 2 nucleotides in exon 5 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 has been reported in individuals affected with Wilson disease (PMID: 17317524, 23518715, 27398169, 34240825, 34400371, 34470610; DOI:10.1134/S1022795419120020). In a family described by Coffey et al, 2013, this variant was found in the compound heterozygous state in a father affected with Wilson disease and an unaffected mother who carried a different variant (p.Val1234Phe). The p.Ile582Argfs*25 variant was identified in the compound heterozygous state in one of their daughters who was affected with Wilson disease and in the heterozygous state in their other daughter who was not affected. This variant has been identified in 6/280960 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	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 11, 2020	The p.Ile582ArgfsX25 variant in ATP7B has been reported in at least 4 individuals with Wilson disease who were compound heterozygous for a second pathogenic variant (Coffey 2013, Hua 2016, Lepori 2007, Loudianos 1999, Thomas 1995). It has been identified in 0.005% (7/128706) of European chromosomes by gnomAD (http://gnomad.broadinstitute.org). This variant is predicted to cause a frameshift, which alters the protein’s amino acid sequence beginning at position 582 and leads to a premature termination codon 25 amino acids downstream. This alteration is then 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, PM3_Strong, PM2, PP4. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Sep 05, 2023	For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. This sequence change creates a premature translational stop signal (p.Ile582Argfs*25) 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 (rs753962912, gnomAD 0.005%). This premature translational stop signal has been observed in individuals with Wilson disease (PMID: 17317524, 17949296, 23518715, 27398169). ClinVar contains an entry for this variant (Variation ID: 189112). -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Dec 31, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 28, 2024	- -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago	Mar 30, 2021	ATP7B NM_000053.3 exon 5 p.Ile582Argfs*25 (1745_1746del): This variant has been reported in the literature in multiple individuals with Wilson disease (Thomas 1995 PMID:7626145, Chappuis 2007 PMID:17317524, Lepori 2007 PMID:17949296, Coffey 2013 PMID:23518715, Hua 2016 PMID:27398169). This variant is also present in 0.004% (6/128706) of European alleles in the Genome Aggregation Database (https://gnomad.broadinstitute.org/variant/13-52539130-CTA-C). Please note, disease causing variants may be present in control databases at low frequencies, reflective of the general population, carrier status, and/or variable expressivity. This variant is present in ClinVar, with multiple labs classifying this variant as pathogenic or Likely Pathogenic (Variation ID:189112). Evolutionary conservation and computational predictive tools for this variant are limited or unavailable. This variant creates a premature stop codon 25 amino acids downstream from this location which results in an absent or abnormal protein. Loss of function variants are a known mechanism of disease for this gene (Buiakova 1999 PMID:10441329). In summary, this variant is classified as pathogenic based on the data above. -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 04, 2020	PVS1, PS4_moderate, PM2, PP4 -
Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 28, 2016	- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 25, 2017

The c.1745_1746delTA pathogenic mutation, located in coding exon 5 of the ATP7B gene, results from a deletion of two nucleotides at nucleotide positions 1745 to 1746, causing a translational frameshift with a predicted alternate stop codon (p.I582Rfs*25). This mutation has been detected in multiple individuals with Wilson disease (Chappuis P et al. J Trace Elem Med Biol, 2007 Jan;21:37-42; Coffey AJ et al. Brain, 2013 May;136:1476-87; Hua R et al. Am J Transl Res, 2016 Jun;8:2851-61). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Spastic ataxia

Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris

Jul 12, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.42

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.42

Position offset: -1

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