rs1061472

chr13-51950352-T-Cchr13-51950352-T-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_000053.4(ATP7B):c.2495A>G(p.Lys832Arg) variant causes a missense change. The variant allele was found at a frequency of 0.562 in 1,613,790 control chromosomes in the GnomAD database, including 256,999 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K832T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.54 (22333 hom., cov: 31)
  • Exomes 𝑓: 0.56 (234666 hom.)
• Consequence: ATP7B NM_000053.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:19
• Conservation: PhyloP100: 6.19

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 Benign. Variant got -18 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000053.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.0037171245).
• BP6: Variant 13-51950352-T-C is Benign according to our data. Variant chr13-51950352-T-C is described in ClinVar as [Benign]. Clinvar id is 35707.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51950352-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.572 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP7B	NM_000053.4	c.2495A>G	p.Lys832Arg	missense_variant	10/21	ENST00000242839.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP7B	ENST00000242839.10	c.2495A>G	p.Lys832Arg	missense_variant	10/21	1	NM_000053.4	P1

Frequencies

GnomAD3 genomes AF: 0.540 AC: 81944 AN: 151884 Hom.: 22328 Cov.: 31

Gnomad AFR AF: 0.493

Gnomad AMI AF: 0.404

Gnomad AMR AF: 0.507

Gnomad ASJ AF: 0.565

Gnomad EAS AF: 0.404

Gnomad SAS AF: 0.514

Gnomad FIN AF: 0.599

Gnomad MID AF: 0.630

Gnomad NFE AF: 0.577

Gnomad OTH AF: 0.565

GnomAD3 exomes AF: 0.539 AC: 134395 AN: 249370 Hom.: 36684 AF XY: 0.542 AC XY: 73388 AN XY: 135292

Gnomad AFR exome AF: 0.486

Gnomad AMR exome AF: 0.491

Gnomad ASJ exome AF: 0.570

Gnomad EAS exome AF: 0.396

Gnomad SAS exome AF: 0.510

Gnomad FIN exome AF: 0.607

Gnomad NFE exome AF: 0.574

Gnomad OTH exome AF: 0.563

GnomAD4 exome AF: 0.565 AC: 825260 AN: 1461788 Hom.: 234666 Cov.: 71 AF XY: 0.564 AC XY: 409857 AN XY: 727186

Gnomad4 AFR exome AF: 0.495

Gnomad4 AMR exome AF: 0.496

Gnomad4 ASJ exome AF: 0.569

Gnomad4 EAS exome AF: 0.401

Gnomad4 SAS exome AF: 0.509

Gnomad4 FIN exome AF: 0.602

Gnomad4 NFE exome AF: 0.578

Gnomad4 OTH exome AF: 0.561

GnomAD4 genome AF: 0.539 AC: 81991 AN: 152002 Hom.: 22333 Cov.: 31 AF XY: 0.538 AC XY: 39989 AN XY: 74290

Gnomad4 AFR AF: 0.493

Gnomad4 AMR AF: 0.507

Gnomad4 ASJ AF: 0.565

Gnomad4 EAS AF: 0.405

Gnomad4 SAS AF: 0.515

Gnomad4 FIN AF: 0.599

Gnomad4 NFE AF: 0.577

Gnomad4 OTH AF: 0.566

Alfa AF: 0.563 Hom.: 58409

Bravo AF: 0.532

TwinsUK AF: 0.575 AC: 2132

ALSPAC AF: 0.582 AC: 2242

ESP6500AA AF: 0.484 AC: 2050

ESP6500EA AF: 0.586 AC: 4978

ExAC AF: 0.537 AC: 65059

Asia WGS AF: 0.504 AC: 1750 AN: 3478

EpiCase AF: 0.583

EpiControl AF: 0.582

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:19

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Wilson disease Benign:11

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 05, 2018	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 08, 2022	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing;curation	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2011	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	May 31, 2018	This variant is interpreted as a Benign - Stand Alone, for Wilson disease, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: BA1 => Allele frequency is >5% in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. -

not specified Benign:7

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 27, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 05, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

not provided Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Department of Pathology and Laboratory Medicine, Sinai Health System

-

multiple AR variants in same gene - keep for nowAllele frequency is common in at least one population database (frequency: 60.857% in ExAC) based on the frequency threshold of 2.434% for this gene.Variant was observed in a homozygous state in population databases more than expected for disease.10 reputable source/s reports the variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation. -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 01, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Uncertain	-0.080
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.74	D;D;.;.;.;.
Eigen	Benign	0.16
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.81	T;T;T;T;T;T
MetaRNN	Benign	0.0037	T;T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.41	N;.;.;.;.;.
MutationTaster	Benign	0.000019	P;P;P;P;P;P;P
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-2.0	N;N;N;N;.;N
REVEL	Uncertain	0.47
Sift	Benign	0.087	T;T;T;T;.;T
Sift4G	Benign	0.12	T;T;T;T;T;T
Polyphen		0.42	B;B;P;B;P;P
Vest4		0.34
MPC		0.087
ClinPred		0.0087	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.34
gMVP		0.79

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

Other links and lift over

dbSNP: rs1061472; hg19: chr13-52524488; COSMIC: COSV54438485; COSMIC: COSV54438485;