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rs137853287

Variant summary

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

The NM_000053.4(ATP7B):c.2304del(p.Met769CysfsTer38) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,892 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: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ATP7B
NM_000053.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:8

Conservation

PhyloP100: -2.18
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]

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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 13-51958361-TG-T is Pathogenic according to our data. Variant chr13-51958361-TG-T is described in ClinVar as [Pathogenic]. Clinvar id is 88957.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51958361-TG-T is described in Lovd as [Pathogenic]. Variant chr13-51958361-TG-T is described in Lovd as [Likely_pathogenic]. Variant chr13-51958361-TG-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
ATP7BNM_000053.4 linkuse as main transcriptc.2304del p.Met769CysfsTer38 frameshift_variant 8/21 ENST00000242839.10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ATP7BENST00000242839.10 linkuse as main transcriptc.2304del p.Met769CysfsTer38 frameshift_variant 8/211 NM_000053.4 P1P35670-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461892
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
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:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.00000378

ClinVar

Significance: 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 submitterclinical testingMendelicsMay 28, 2019- -
Pathogenic, criteria provided, single submitterclinical testingInvitaeDec 02, 2023This sequence change creates a premature translational stop signal (p.Met769Cysfs*38) 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 not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with Wilson disease (PMID: 9554743, 16603785). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 88957). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsOct 01, 2022- -
Pathogenic, criteria provided, single submitterclinical testingGenome-Nilou LabAug 10, 2021- -
Pathogenic, criteria provided, single submitterclinical testingCounsylFeb 21, 2017- -
Pathogenic, criteria provided, single submitterclinical testingAll of Us Research Program, National Institutes of HealthAug 15, 2023This variant deletes 1 nucleotide in exon 8 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 observed in over 10 individuals affected with autosomal recessive Wilson disease (PMID: 9554743, 23982005, 23159873, 31059521, 35782615), including three individuals in the homozygous state (PMID: 19118915) and three individuals in the compound heterozygous state with a second pathogenic ATP7B variant (PMID: 16603785, 25704634, 26799313). This variant has not been identified 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. -
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingAmbry GeneticsJun 14, 2017The c.2304delC pathogenic mutation, located in coding exon 8 of the ATP7B gene, results from a deletion of one nucleotide at nucleotide position 2304, causing a translational frameshift with a predicted alternate stop codon (p.M769Cfs*38). This mutation was first reported in an individual with Wilson disease; however, the second ATP7B alteration was not provided (Kim EK et al. Hum. Mutat., 1998;11:275-8). In a cohort of Chinese Han individuals with Wilson disease, this mutation was detected in conjunction with a second ATP7B alteration; however, the phase was not provided (Liu Y et al. Arch. Med. Res., 2015 Feb;46:164-9). 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. -
not provided Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenAug 01, 2022ATP7B: PVS1, PP1:Strong, PM2, PM3, PP4 -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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.

Other links and lift over

dbSNP: rs137853287; hg19: chr13-52532497; API