rs1801249

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.57 ( 24911 hom., cov: 30)

Exomes 𝑓: 0.58 ( 246937 hom. )

Consequence

ATP7B
NM_000053.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts U:1B:19

Conservation

PhyloP100: 0.0310

Variant links:

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 links:

ATP7B (HGNC:):

ATP7B links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

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 id is 35720.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51941218-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.591 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP7B	NM_000053.4 linkuse as main transcript	c.3419T>C	p.Val1140Ala	missense_variant	16/21	ENST00000242839.10	NP_000044.2	P35670-1B7ZLR4A0A024RDX3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP7B	ENST00000242839.10 linkuse as main transcript	c.3419T>C	p.Val1140Ala	missense_variant	16/21	1	NM_000053.4	ENSP00000242839.5		P35670-1

Frequencies

GnomAD3 genomes

AF:

0.571

AC:

86732

AN:

151764

Hom.:

24894

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.569

AC:

142081

AN:

249554

Hom.:

40962

AF XY:

0.568

AC XY:

76841

AN XY:

135400

show subpopulations

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 SAS exome

AF:

0.521

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.:

AF XY:

0.578

AC XY:

420148

AN XY:

727102

show subpopulations

Gnomad4 AFR exome

AF:

0.559

Gnomad4 AMR exome

AF:

0.635

Gnomad4 ASJ exome

AF:

0.574

Gnomad4 EAS exome

AF:

0.402

Gnomad4 SAS exome

AF:

0.521

Gnomad4 FIN exome

AF:

0.607

Gnomad4 NFE exome

AF:

0.587

Gnomad4 OTH exome

AF:

0.577

GnomAD4 genome

AF:

0.571

AC:

86795

AN:

151882

Hom.:

24911

Cov.:

AF XY:

0.571

AC XY:

42376

AN XY:

74224

show subpopulations

Gnomad4 AFR

AF:

0.556

Gnomad4 AMR

AF:

0.602

Gnomad4 ASJ

AF:

0.569

Gnomad4 EAS

AF:

0.408

Gnomad4 SAS

AF:

0.524

Gnomad4 FIN

AF:

0.602

Gnomad4 NFE

AF:

0.586

Gnomad4 OTH

AF:

0.595

Alfa

AF:

0.574

Hom.:

50171

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:1Benign:19

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Wilson disease

Benign:9

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 05, 2018	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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	Oct 03, 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	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Nov 26, 2011	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 08, 2022	- -

not specified

Benign:8

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 19, 2017	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
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	-	- -
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	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. -

not provided

Uncertain:1Benign: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: 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. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

0.058

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.39

CADD

Benign

7.6

DANN

Benign

0.24

DEOGEN2

Uncertain

0.51

D;T;.;.;.;.;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.0047

LIST_S2

Benign

0.0056

T;T;T;T;T;T;T

MetaRNN

Benign

0.000013

T;T;T;T;T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.15

N;.;.;.;.;.;.

PrimateAI

Benign

0.25

PROVEAN

Benign

0.92

N;N;N;N;N;.;N

REVEL

Benign

0.19

Sift

Benign

0.91

T;T;T;T;T;.;T

Sift4G

Benign

1.0

T;T;T;T;T;T;T

Polyphen

0.0

B;B;B;B;B;B;B

Vest4

0.051

MPC

0.069

ClinPred

0.00030

GERP RS

0.087

Varity_R

0.030

gMVP

0.38

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over