rs371840514

chr13-51946291-G-Achr13-51946291-G-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_000053.4(ATP7B):c.3053C>T(p.Ala1018Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000341 in 1,585,058 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A1018E) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000035 (0 hom.)
• Consequence: ATP7B NM_000053.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 9.93

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 16 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000053.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr13-51946291-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2083623.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.894
• PP5: Variant 13-51946291-G-A is Pathogenic according to our data. Variant chr13-51946291-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 188722.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51946291-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP7B	NM_000053.4	c.3053C>T	p.Ala1018Val	missense_variant	13/21	ENST00000242839.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP7B	ENST00000242839.10	c.3053C>T	p.Ala1018Val	missense_variant	13/21	1	NM_000053.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152216 Hom.: 0 Cov.: 33

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: 0.000207

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000584 AC: 12 AN: 205324 Hom.: 0 AF XY: 0.0000631 AC XY: 7 AN XY: 110960

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000102

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000111

Gnomad FIN exome AF: 0.000111

Gnomad NFE exome AF: 0.0000447

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000349 AC: 50 AN: 1432842 Hom.: 0 Cov.: 31 AF XY: 0.0000338 AC XY: 24 AN XY: 710260

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000747

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000120

Gnomad4 FIN exome AF: 0.0000968

Gnomad4 NFE exome AF: 0.0000292

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152216 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74376

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000227

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000120 AC: 1

ExAC AF: 0.0000415 AC: 5

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Wilson disease Pathogenic:8

Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 26, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 09, 2022	The ATP7B c.3053C>T; p.Ala1018Val variant (rs371840514) is reported in the literature in several individuals affected with Wilson disease, including in the compound heterozygous state with other pathogenic ATP7B variants (Lepori 2007, Loudianos 1998, Mak 2008, Petrasek 2007, Qian 2019, Singh 2019, Vrabelova 2005, Zappu 2008). This variant is also reported in ClinVar (Variation ID: 188722), and is found in the general population with an overall allele frequency of 0.0058% (12/205324 alleles) in the Genome Aggregation Database. The alanine at codon 1018 is moderately conserved, and computational analyses predict that this variant is deleterious (REVEL: 0.890). Based on available information, this variant is considered to be pathogenic. References: Lepori MB et al. Twenty-four novel mutations in Wilson disease patients of predominantly Italian origin. Genet Test. 2007 Fall;11(3):328-32. PMID: 17949296. Loudianos G et al. Further delineation of the molecular pathology of Wilson disease in the Mediterranean population. Hum Mutat. 1998;12(2):89-94. PMID: 9671269. Mak CM et al. Mutational analysis of 65 Wilson disease patients in Hong Kong Chinese: identification of 17 novel mutations and its genetic heterogeneity. J Hum Genet. 2008;53(1):55-63. PMID: 18034201. Petrasek J et al. Revised King's College score for liver transplantation in adult patients with Wilson's disease. Liver Transpl. 2007 Jan;13(1):55-61. PMID: 17154398. Qian Z et al. Novel mutations found in the ATP7B gene in Chinese patients with Wilson's disease. Mol Genet Genomic Med. 2019 May;7(5):e649. PMID: 30884209. Singh N et al. Genetic analysis of ATP7B in 102 south Indian families with Wilson disease. PLoS One. 2019 May 6;14(5):e0215779. PMID: 31059521. Vrabelova S et al. Mutation analysis of the ATP7B gene and genotype/phenotype correlation in 227 patients with Wilson disease. Mol Genet Metab. 2005 Sep-Oct;86(1-2):277-85. PMID: 15967699. Zappu A et al. High incidence and allelic homogeneity of Wilson disease in 2 isolated populations: a prerequisite for efficient disease prevention programs. J Pediatr Gastroenterol Nutr. 2008 Sep;47(3):334-8. PMID: 18728530. -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Mar 17, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jan 16, 2023	Variant summary: ATP7B c.3053C>T (p.Ala1018Val) results in a non-conservative amino acid change located in the P-type ATPase, haloacid dehalogenase domain (IPR044492) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.8e-05 in 205324 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in ATP7B causing Wilson Disease (5.8e-05 vs 0.0054). c.3053C>T has been reported in the literature in multiple individuals affected with Wilson Disease (Loudianos_1998, Vrabelova_2005, Dong_2016, Singh_2019, Couchonnal_2021, etc.). These data indicate that the variant is very likely to be associated with disease. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. The 4 laboratories classified the variant as likely pathogenic (n=2), or pathogenic (n=2). Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 13, 2023	This missense variant replaces alanine with valine at codon 1018 of the ATP7B protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been observed in many individuals affected with autosomal recessive Wilson disease, with some cases confirmed in the compound heterozygous state (PMID: 9671269, 10502776, 15967699, 17154398, 17949296, 18034201, 22677543, 24146181, 24718822, 27022412, 30884209, 31059521, 33640437, 34400371, 35535059; ClinVar SCV000948175.5), indicating that this variant contributes to disease. This variant has been identified in 12/205324 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 12, 2023	This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1018 of the ATP7B protein (p.Ala1018Val). This variant is present in population databases (rs371840514, gnomAD 0.01%). This missense change has been observed in individual(s) with Wilson disease (PMID: 17154398, 30884209, 31059521; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 188722). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ATP7B protein function with a negative predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 10, 2022	- -

ATP7B-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 06, 2023

The ATP7B c.3053C>T variant is predicted to result in the amino acid substitution p.Ala1018Val. This variant has been reported in several individuals with Wilson disease, though clinical and variant phase data was not well documented in some of these individuals (Loudianos et al. 1998. PubMed ID: 9671269; Table S2, Schushan et al. 2012. PubMed ID: 22692182; Couchonnal et al. 2021. PubMed ID: 34400371; Table S4, Zhang et al. 2022. PubMed ID: 35220961; Mak et al. 2007. PubMed ID: 18034201; Petrasek et al. 2007. PubMed ID: 17154398; Singh et al. 2019. PubMed ID: 31059521; Dong et al. 2016. PubMed ID: 27022412). However, in at least 2 individuals, clinical, laboratory and histological findings were consistent with Wilson disease; including one individual diagnosed with later onset Wilson disease who was homozygous for the variant (Stalke et al. 2023. PubMed ID: 37157876, Annamalai et al. 2022. PubMed ID: 35580721). In vitro functional studies demonstrate this variant leads to a not statistically significant reduced protein levels and reduced copper export capacity, but in similar range to a well established pathogenic missense variant (Stalke et al. 2023. PubMed ID: 37157876). This variant is reported in 0.011% of alleles in individuals of South Asian descent in gnomAD (http://gnomad.broadinstitute.org/variant/13-52520427-G-A). We classify this variant as likely pathogenic. -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 04, 2021

Reported in multiple individuals with Wilson disease with no information provided regarding the presence of a second ATP7B variant (Loudianos et al., 1998; Loudianos et al., 1999; Vrabelova et al., 2005; Lepori et al., 2007; Zappu et al., 2008; Mak et al., 2008; Chen et al., 2019); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30275481, 31246682, 30655162, 17949296, 22692182, 17154398, 18034201, 23486543, 18728530, 15967699, 10502776, 9671269, 30556376, 30884209) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.53
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D;T;.;.;.;.
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D
M_CAP	Pathogenic	0.65	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Uncertain	2.2	M;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.3	D;D;D;D;D;.
REVEL	Pathogenic	0.89
Sift	Benign	0.060	T;D;T;T;D;.
Sift4G	Uncertain	0.051	T;D;T;T;T;D
Polyphen		1.0	D;D;D;B;D;D
Vest4		0.96
MVP		0.95
MPC		0.36
ClinPred		0.75	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.62
gMVP		0.87

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: rs371840514; hg19: chr13-52520427;