rs1801243

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.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 (★★).

Frequency

Genomes: 𝑓 0.40 ( 13523 hom., cov: 33)

Exomes 𝑓: 0.48 ( 170543 hom. )

Consequence

ATP7B
NM_000053.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:20

Conservation

PhyloP100: -1.55

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:

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=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	Protein	UniProt
ATP7B	NM_000053.4 linkuse as main transcript	c.1216T>G	p.Ser406Ala	missense_variant	2/21	ENST00000242839.10	NP_000044.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP7B	ENST00000242839.10 linkuse as main transcript	c.1216T>G	p.Ser406Ala	missense_variant	2/21	1	NM_000053.4	ENSP00000242839	P1	P35670-1

Frequencies

GnomAD3 genomes

AF:

0.401

AC:

60992

AN:

152042

Hom.:

13529

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.476

AC XY:

345879

AN XY:

727236

show subpopulations

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.:

AF XY:

0.404

AC XY:

30026

AN XY:

74388

show subpopulations

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:1Benign:20

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:9

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University 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, 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	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

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, 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, 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, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 05, 2018	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

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: 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. -
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

0.062

BayesDel_addAF

Benign

-0.60

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

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

MutationAssessor

Benign

0.69

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

MutationTaster

Benign

1.0

P;P;P;P;P;P;P

PrimateAI

Benign

0.27

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

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

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