13-51941218-A-G

Variant names:

• chr13-51941218-A-G
• rs1801249
• NM_000053.4:c.3419T>C

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1 PP2 BP4_Strong BP6_Very_Strong BA1

The NM_000053.4(ATP7B):​c.3419T>C​(p.Val1140Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.579 in 1,613,484 control chromosomes in the GnomAD database, including 271,848 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1140S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.57 (24911 hom., cov: 30)
  • Exomes 𝑓: 0.58 (246937 hom.)
• Consequence: ATP7B NM_000053.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:19
• Conservation: PhyloP100: 0.0310
• Publications: 80 publications found

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 Gene-Disease associations (from GenCC):

• Wilson disease

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 10 uncertain in NM_000053.4
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 198 curated pathogenic missense variants (we use a threshold of 10). The gene has 32 curated benign missense variants. Gene score misZ: -0.88091 (below the threshold of 3.09). Trascript score misZ: 0.82063 (below the threshold of 3.09). GenCC associations: The gene is linked to Wilson disease.
• BP4: Computational evidence support a benign effect (MetaRNN=1.2938263E-5).
• BP6: Variant 13-51941218-A-G is Benign according to our data. Variant chr13-51941218-A-G is described in ClinVar as Benign. ClinVar VariationId is 35720.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.591 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000053.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP7B	NM_000053.4	MANE Select	c.3419T>C	p.Val1140Ala	missense	Exon 16 of 21	NP_000044.2
	ATP7B	NM_001406511.1		c.3419T>C	p.Val1140Ala	missense	Exon 17 of 22	NP_001393440.1
	ATP7B	NM_001406512.1		c.3419T>C	p.Val1140Ala	missense	Exon 17 of 22	NP_001393441.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ATP7B	ENST00000242839.10	TSL:1 MANE Select	c.3419T>C	p.Val1140Ala	missense	Exon 16 of 21	ENSP00000242839.5
	ATP7B	ENST00000634844.1	TSL:1	c.3275T>C	p.Val1092Ala	missense	Exon 16 of 21	ENSP00000489398.1
	ATP7B	ENST00000418097.7	TSL:1	c.3224T>C	p.Val1075Ala	missense	Exon 15 of 20	ENSP00000393343.2

Frequencies

GnomAD3 genomes AF: 0.571 AC: 86732 AN: 151764 Hom.: 24894 Cov.: 30

Gnomad AFR AF: 0.556

Gnomad AMI AF: 0.430

Gnomad AMR AF: 0.602

Gnomad ASJ AF: 0.569

Gnomad EAS AF: 0.407

Gnomad SAS AF: 0.523

Gnomad FIN AF: 0.602

Gnomad MID AF: 0.642

Gnomad NFE AF: 0.587

Gnomad OTH AF: 0.593

GnomAD2 exomes AF: 0.569 AC: 142081 AN: 249554 AF XY: 0.568

Gnomad AFR exome AF: 0.550

Gnomad AMR exome AF: 0.637

Gnomad ASJ exome AF: 0.575

Gnomad EAS exome AF: 0.397

Gnomad FIN exome AF: 0.610

Gnomad NFE exome AF: 0.583

Gnomad OTH exome AF: 0.585

GnomAD4 exome AF: 0.579 AC: 846900 AN: 1461602 Hom.: 246937 Cov.: 56 AF XY: 0.578 AC XY: 420148 AN XY: 727102

African (AFR) AF: 0.559 AC: 18710 AN: 33476

American (AMR) AF: 0.635 AC: 28420 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.574 AC: 15001 AN: 26134

East Asian (EAS) AF: 0.402 AC: 15953 AN: 39694

South Asian (SAS) AF: 0.521 AC: 44936 AN: 86254

European-Finnish (FIN) AF: 0.607 AC: 32397 AN: 53406

Middle Eastern (MID) AF: 0.633 AC: 3652 AN: 5766

European-Non Finnish (NFE) AF: 0.587 AC: 652963 AN: 1111764

Other (OTH) AF: 0.577 AC: 34868 AN: 60386

GnomAD4 genome AF: 0.571 AC: 86795 AN: 151882 Hom.: 24911 Cov.: 30 AF XY: 0.571 AC XY: 42376 AN XY: 74224

African (AFR) AF: 0.556 AC: 22996 AN: 41390

American (AMR) AF: 0.602 AC: 9188 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.569 AC: 1974 AN: 3472

East Asian (EAS) AF: 0.408 AC: 2100 AN: 5152

South Asian (SAS) AF: 0.524 AC: 2517 AN: 4808

European-Finnish (FIN) AF: 0.602 AC: 6349 AN: 10550

Middle Eastern (MID) AF: 0.639 AC: 188 AN: 294

European-Non Finnish (NFE) AF: 0.586 AC: 39839 AN: 67930

Other (OTH) AF: 0.595 AC: 1253 AN: 2106

Alfa AF: 0.573 Hom.: 99814

Bravo AF: 0.573

TwinsUK AF: 0.586 AC: 2173

ALSPAC AF: 0.590 AC: 2274

ESP6500AA AF: 0.548 AC: 2112

ESP6500EA AF: 0.591 AC: 4888

ExAC AF: 0.565 AC: 68274

Asia WGS AF: 0.529 AC: 1836 AN: 3478

EpiCase AF: 0.591

EpiControl AF: 0.591

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:19

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Wilson disease Benign:9

Mar 05, 2018

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 01, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 03, 2024

All of Us Research Program, National Institutes of Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 26, 2011

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

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Mar 08, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not specified Benign:8

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Jan 05, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Oct 19, 2017

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Uncertain:1 Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

multiple AR variants in same gene - keep for nowAllele frequency is common in at least one population database (frequency: 64.181% 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.

Inborn genetic diseases Benign:1

Jul 01, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	7.6
DANN	Benign	0.24
DEOGEN2	Uncertain	0.51	D
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.0047	N
LIST_S2	Benign	0.0056	T
MetaRNN	Benign	0.000013	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.15	N
PhyloP100		0.031
PrimateAI	Benign	0.25	T
PROVEAN	Benign	0.92	N
REVEL	Benign	0.19
Sift	Benign	0.91	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.051
MPC		0.069
ClinPred		0.00030	T
GERP RS		0.087
Varity_R		0.030
gMVP		0.38
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1801249; hg19: chr13-52515354; COSMIC: COSV54438812; COSMIC: COSV54438812;