13-51970669-C-G

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.1366G>C(p.Val456Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.465 in 1,613,902 control chromosomes in the GnomAD database, including 178,885 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict 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. Synonymous variant affecting the same amino acid position (i.e. V456V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.41 (13491 hom., cov: 32)
  • Exomes 𝑓: 0.47 (165394 hom.)
• Consequence: ATP7B NM_000053.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts U:1 B:17
• Conservation: PhyloP100: -0.911

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=1.083074E-4).
• BP6: Variant 13-51970669-C-G is Benign according to our data. Variant chr13-51970669-C-G is described in ClinVar as [Benign]. Clinvar id is 35702.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51970669-C-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.484 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP7B	NM_000053.4	c.1366G>C	p.Val456Leu	missense_variant	3/21	ENST00000242839.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP7B	ENST00000242839.10	c.1366G>C	p.Val456Leu	missense_variant	3/21	1	NM_000053.4	P1

Frequencies

GnomAD3 genomes AF: 0.407 AC: 61848 AN: 151970 Hom.: 13493 Cov.: 32

Gnomad AFR AF: 0.233

Gnomad AMI AF: 0.376

Gnomad AMR AF: 0.410

Gnomad ASJ AF: 0.430

Gnomad EAS AF: 0.487

Gnomad SAS AF: 0.353

Gnomad FIN AF: 0.528

Gnomad MID AF: 0.487

Gnomad NFE AF: 0.488

Gnomad OTH AF: 0.464

GnomAD3 exomes AF: 0.440 AC: 109640 AN: 249182 Hom.: 25025 AF XY: 0.441 AC XY: 59610 AN XY: 135194

Gnomad AFR exome AF: 0.226

Gnomad AMR exome AF: 0.388

Gnomad ASJ exome AF: 0.436

Gnomad EAS exome AF: 0.483

Gnomad SAS exome AF: 0.347

Gnomad FIN exome AF: 0.537

Gnomad NFE exome AF: 0.484

Gnomad OTH exome AF: 0.472

GnomAD4 exome AF: 0.472 AC: 689334 AN: 1461814 Hom.: 165394 Cov.: 61 AF XY: 0.469 AC XY: 341034 AN XY: 727208

Gnomad4 AFR exome AF: 0.228

Gnomad4 AMR exome AF: 0.393

Gnomad4 ASJ exome AF: 0.433

Gnomad4 EAS exome AF: 0.476

Gnomad4 SAS exome AF: 0.344

Gnomad4 FIN exome AF: 0.527

Gnomad4 NFE exome AF: 0.490

Gnomad4 OTH exome AF: 0.467

GnomAD4 genome AF: 0.407 AC: 61856 AN: 152088 Hom.: 13491 Cov.: 32 AF XY: 0.409 AC XY: 30433 AN XY: 74340

Gnomad4 AFR AF: 0.232

Gnomad4 AMR AF: 0.409

Gnomad4 ASJ AF: 0.430

Gnomad4 EAS AF: 0.487

Gnomad4 SAS AF: 0.353

Gnomad4 FIN AF: 0.528

Gnomad4 NFE AF: 0.488

Gnomad4 OTH AF: 0.463

Alfa AF: 0.430 Hom.: 4418

Bravo AF: 0.393

TwinsUK AF: 0.490 AC: 1818

ALSPAC AF: 0.496 AC: 1913

ESP6500AA AF: 0.224 AC: 887

ESP6500EA AF: 0.492 AC: 4068

ExAC AF: 0.434 AC: 52469

Asia WGS AF: 0.423 AC: 1466 AN: 3478

EpiCase AF: 0.488

EpiControl AF: 0.486

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:17

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:8

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 27, 2016	- -
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	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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	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	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -

Wilson disease Benign:8

Benign, no assertion criteria provided	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 26, 2011	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
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	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	-	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -

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: 53.754% 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

Aug 02, 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	0.075
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.32
Cadd	Benign	5.0
Dann	Benign	0.87
DEOGEN2	Benign	0.28	T;T;.;.;.;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.039	N
LIST_S2	Benign	0.56	T;T;T;T;T;T
MetaRNN	Benign	0.00011	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	-0.18	N;N;N;N;.;N
REVEL	Benign	0.12
Sift	Benign	0.60	T;T;T;T;.;T
Sift4G	Benign	0.63	T;T;T;T;T;T
Polyphen		0.0010	B;B;B;B;B;B
Vest4		0.037
MutPred		0.10		Loss of loop (P = 0.0512);Loss of loop (P = 0.0512);Loss of loop (P = 0.0512);.;Loss of loop (P = 0.0512);Loss of loop (P = 0.0512);
MPC		0.058
ClinPred		0.0082	T
GERP RS		-0.18
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.078
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs1801244; hg19: chr13-52544805; COSMIC: COSV54435164; COSMIC: COSV54435164;