rs1801243

Positions:

• chr13-51974004-A-C
• chr13-51974004-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000053.4(ATP7B):​c.1216T>G​(p.Ser406Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.471 in 1,614,028 control chromosomes in the GnomAD database, including 184,066 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S406T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.40 (13523 hom., cov: 33)
  • Exomes 𝑓: 0.48 (170543 hom.)
• Consequence: ATP7B NM_000053.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1 B:19
• Conservation: PhyloP100: -1.55

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=4.1596646E-5).
• BP6: Variant 13-51974004-A-C is Benign according to our data. Variant chr13-51974004-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 35701.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51974004-A-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.524 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP7B	NM_000053.4	c.1216T>G	p.Ser406Ala	missense_variant	2/21	ENST00000242839.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP7B	ENST00000242839.10	c.1216T>G	p.Ser406Ala	missense_variant	2/21	1	NM_000053.4	P1

Frequencies

GnomAD3 genomes AF: 0.401 AC: 60992 AN: 152042 Hom.: 13529 Cov.: 33

Gnomad AFR AF: 0.192

Gnomad AMI AF: 0.377

Gnomad AMR AF: 0.404

Gnomad ASJ AF: 0.442

Gnomad EAS AF: 0.541

Gnomad SAS AF: 0.359

Gnomad FIN AF: 0.538

Gnomad MID AF: 0.475

Gnomad NFE AF: 0.495

Gnomad OTH AF: 0.455

GnomAD3 exomes AF: 0.445 AC: 111028 AN: 249516 Hom.: 25851 AF XY: 0.446 AC XY: 60391 AN XY: 135366

Gnomad AFR exome AF: 0.184

Gnomad AMR exome AF: 0.387

Gnomad ASJ exome AF: 0.440

Gnomad EAS exome AF: 0.533

Gnomad SAS exome AF: 0.352

Gnomad FIN exome AF: 0.545

Gnomad NFE exome AF: 0.490

Gnomad OTH exome AF: 0.471

GnomAD4 exome AF: 0.478 AC: 698979 AN: 1461868 Hom.: 170543 Cov.: 73 AF XY: 0.476 AC XY: 345879 AN XY: 727236

Gnomad4 AFR exome AF: 0.186

Gnomad4 AMR exome AF: 0.391

Gnomad4 ASJ exome AF: 0.439

Gnomad4 EAS exome AF: 0.525

Gnomad4 SAS exome AF: 0.350

Gnomad4 FIN exome AF: 0.535

Gnomad4 NFE exome AF: 0.497

Gnomad4 OTH exome AF: 0.471

GnomAD4 genome AF: 0.401 AC: 60988 AN: 152160 Hom.: 13523 Cov.: 33 AF XY: 0.404 AC XY: 30026 AN XY: 74388

Gnomad4 AFR AF: 0.192

Gnomad4 AMR AF: 0.404

Gnomad4 ASJ AF: 0.442

Gnomad4 EAS AF: 0.540

Gnomad4 SAS AF: 0.359

Gnomad4 FIN AF: 0.538

Gnomad4 NFE AF: 0.495

Gnomad4 OTH AF: 0.454

Alfa AF: 0.475 Hom.: 40907

Bravo AF: 0.385

TwinsUK AF: 0.494 AC: 1833

ALSPAC AF: 0.508 AC: 1956

ESP6500AA AF: 0.186 AC: 720

ESP6500EA AF: 0.502 AC: 4158

ExAC AF: 0.438 AC: 52986

Asia WGS AF: 0.429 AC: 1489 AN: 3478

EpiCase AF: 0.494

EpiControl AF: 0.491

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1 Benign:19

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:9

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	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 08, 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, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 27, 2016	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Wilson disease Benign:9

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 18, 2011	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 05, 2018	- -
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	Genome-Nilou Lab	Jul 01, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

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: 54.463% 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

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	0.062
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	7.6
DANN	Uncertain	0.98
DEOGEN2	Benign	0.42	T;T;.;.;.;.;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.077	N
LIST_S2	Benign	0.22	T;T;T;T;T;T;T
MetaRNN	Benign	0.000042	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N;.;N;.;.;.;.
MutationTaster	Benign	1.0	P;P;P;P;P;P;P
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.20	N;N;N;N;N;.;N
REVEL	Benign	0.049
Sift	Benign	0.75	T;T;T;T;T;.;T
Sift4G	Benign	0.77	T;T;T;T;T;T;T
Polyphen		0.0010	B;B;B;B;B;B;B
Vest4		0.018
MPC		0.053
ClinPred		0.0092	T
GERP RS		-0.027
Varity_R		0.051
gMVP		0.19

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: rs1801243; hg19: chr13-52548140; COSMIC: COSV54438507; COSMIC: COSV54438507;