Variant rs749363958 details in Genebe, Genetics Data Aggregator

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:

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 188 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP7B	NM_000053.4 linkuse as main transcript	c.19_20del	p.Gln7AspfsTer14	frameshift_variant	1/21	ENST00000242839.10	NP_000044.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP7B	ENST00000242839.10 linkuse as main transcript	c.19_20del	p.Gln7AspfsTer14	frameshift_variant	1/21	1	NM_000053.4	ENSP00000242839	P1	P35670-1

Frequencies

GnomAD3 genomes

AF:

0.000151

AC:

AN:

152262

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000235

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000152

AC:

AN:

249432

Hom.:

AF XY:

0.000177

AC XY:

AN XY:

135350

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000497

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000654

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000265

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.000108

AC:

158

AN:

1461862

Hom.:

AF XY:

0.000124

AC XY:

AN XY:

727222

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.000536

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.000104

Gnomad4 OTH exome

AF:

0.000199

GnomAD4 genome

AF:

0.000151

AC:

AN:

152380

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74512

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000235

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000174

Hom.:

Bravo

AF:

0.000170

EpiCase

AF:

0.000218

EpiControl

AF:

0.000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:8

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Wilson disease

Pathogenic:3Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 25, 2024	This sequence change creates a premature translational stop signal (p.Gln7Aspfs*14) 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 (rs749363958, gnomAD 0.05%). This premature translational stop signal has been observed in individual(s) with Wilson disease (PMID: 15967699). ClinVar contains an entry for this variant (Variation ID: 419611). For these reasons, this variant has been classified as Pathogenic. -
Uncertain significance, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	Mar 01, 2023	The frameshift c.19_20del(p.Gln7AspfsTer14) variant in ATP7B gene has been reported previously to be correlating with Wilson disease (Vrabelova et al. 2005), and has also been reported in both homozygous and compound heterozygous state in individuals asymptomatic for Wilson disease (Loudianos et al. 2016; Stalke et al. 2019). The p.Gln7AspfsTer14 variant is reported with an allele frequency of 0.02% in the gnomAD exomes database and is novel (not in any individuals) in 1000 Genomes database. This variant has been reported to the ClinVar database as Pathogenic / Likely Pathogenic / Uncertain Siginificance. This variant causes a frameshift starting with codon Glutamine 7, changes this amino acid to Aspartic Acid residue, and creates a premature Stop codon at position 14 of the new reading frame, denoted p.Gln7AspfsTer14. Loss of function variants have been previously reported to be disease causing. However, experimental evidence suggests that this variant's mRNA and protein is expressed in amounts comparable to the wild-type and the copper export capacity is also comparable to the wild-type, indicating that this variant is able to bypass non-sense mediated decay by translation reinitiation (Stalke et al. 2019). For these reasons, this variant is classified as a Variant of Uncertain Significance (VUS). -
Uncertain significance, criteria provided, single submitter	clinical testing	Counsyl	May 30, 2017	- -
Pathogenic, criteria provided, single submitter	curation	Laboratory of Medical Genetics, National & Kapodistrian University of Athens	Feb 01, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Jan 11, 2024	This variant deletes 2 nucleotides in exon 1 of the ATP7B gene, creating a frameshift and premature translation stop signal. While this variant is expected to result in nonsense-mediated mRNA decay, clinical findings and functional study results indicate that the effect of this variant appears to be mitigated, presumably by an alternate translation initiation. This variant has been reported as homozygous in a 5-year-old girl who exhibited no symptoms of Wilson disease, no abnormalities in liver biopsy, and ATP7B mRNA expression levels in the liver comparable to healthy controls (PMID: 30723317). When a minigene construct carrying this variant was overexpressed in HEK293T cells, it resulted in ATP7B mRNA and protein expression comparable to wild-type in size and amount, as well as normal copper export capacity (PMID: 30723317). This variant has also been reported in an asymptomatic adult in compound heterozygous state with a known pathogenic variant in the same gene (PMID: 26752957). These observations indicate that the predicted loss of ATP7B function due to this variant can be bypassed, presumably by alternate translation initiation using a downstream methionine. This variant has been reported in additional individuals affected with Wilson disease with unspecified second mutation (PMID: 15967699, 34620762). This variant has been identified in 39/280828 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -

not provided

Pathogenic:1Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 20, 2024	Reported homozygous in a female pediatric patient with no symptoms of Wilson disease or abnormalities on liver biopsy (PMID: 30723317); Expression of mRNA in liver cells of a patient homozygous for the variant was in the range of healthy controls and in-vitro expression assays found mRNA and protein levels comparable to wild type, suggesting that the variant may bypass nonsense-mediated mRNA decay (NMD) allowing normal copper export (PMID: 30723317); This variant is associated with the following publications: (PMID: 18371106, 29649982, 31169307, 23486543, 30291343, 31980526, 26752957, 15967699, 30723317, 36437915, 34620762, 30476936) -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 27, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2016	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Apr 04, 2023

Variant summary: ATP7B c.19_20delCA (p.Gln7AspfsX14) 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. However, a functional study (Stalke_2019) found the variant mRNA and protein is expressed in size and amount comparable to wild-type while, copper export capacity was also comparable to wild-type; these results indicate that c.19_20del in ATP7B is able to bypass NMD by translation reinitiation. The variant allele was found at a frequency of 0.00015 in 249432 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in ATP7B causing Wilson Disease (0.00015 vs 0.0054), allowing no conclusion about variant significance. c.19_20delCA has been reported in the literature in a individuals affected with Wilson Disease, however with limited information (i.e. second allele not reported/specified) in one case (Vrabelova_2005) and in two individuals diagnosed with the hepatic form of Wilson Disease who were compound heterozygous together with a pathogenic variant (p.H1069Q), but who had ATP7B peptide levels (assayed from dried blood spots) that were mostly within or near the normal range (Collins_2021). In addition, multiple individuals, one compound heterozygote adult (Loudianos_2016) and one homozygous adolescent (Stalke_2019), were found to be asymptomatic. Thus, these reports do not provide unequivocal conclusions about association of the variant with Wilson Disease. Six submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments, classifying the variant as either VUS (n=3) or likely pathogenic (n=2)/pathogenic (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. -

ATP7B-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 12, 2022

The ATP7B c.19_20delCA variant is predicted to result in a frameshift and premature protein termination (p.Gln7Aspfs*14). This variant has been reported in an individual with Wilson disease (Vrabelova et al. 2005. PubMed ID: 15967699). Of note, this variant was also detected in the compound heterozygous state in an asymptomatic adult patient (Loudianos et al. 2016. PubMed ID: 26752957) and in the homozygous state in an asymptomatic adolescent patient (Stalke et al. 2019. PubMed ID: 30723317). Additional function studies showed that this variant bypasses nonsense-mediated mRNA decay and protein function is similar to wild-type (Stalke et al. 2019. PubMed ID: 30723317). This variant is reported in 0.048% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/13-52585453-CTG-C). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

Below is the list of publications found by LitVar. It may be empty.

rs749363958

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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