rs7334118

Positions:

chr13-51939130-T-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The ENST00000242839.10(ATP7B):c.3620A>G(p.His1207Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0154 in 1,614,212 control chromosomes in the GnomAD database, including 768 homozygotes. In-silico tool predicts 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. H1207Y) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.027 ( 122 hom., cov: 33)

Exomes 𝑓: 0.014 ( 646 hom. )

Consequence

ATP7B
ENST00000242839.10 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:19

Conservation

PhyloP100: 3.46

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 -18 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in ENST00000242839.10

BP4

Computational evidence support a benign effect (MetaRNN=0.0022899806).

BP6

Variant 13-51939130-T-C is Benign according to our data. Variant chr13-51939130-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 35724.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51939130-T-C is described in Lovd as [Benign]. Variant chr13-51939130-T-C is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0889 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.3620A>G	p.His1207Arg	missense_variant	17/21	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.3620A>G	p.His1207Arg	missense_variant	17/21	1	NM_000053.4	ENSP00000242839	P1	P35670-1

Frequencies

GnomAD3 genomes

AF:

0.0273

AC:

4153

AN:

152214

Hom.:

122

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0472

Gnomad AMI

AF:

0.0219

Gnomad AMR

AF:

0.0931

Gnomad ASJ

AF:

0.00375

Gnomad EAS

AF:

0.00154

Gnomad SAS

AF:

0.00910

Gnomad FIN

AF:

0.00160

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.00910

Gnomad OTH

AF:

0.0220

GnomAD3 exomes

AF:

0.0296

AC:

7396

AN:

249590

Hom.:

461

AF XY:

0.0244

AC XY:

3302

AN XY:

135400

show subpopulations

Gnomad AFR exome

AF:

0.0488

Gnomad AMR exome

AF:

0.148

Gnomad ASJ exome

AF:

0.00496

Gnomad EAS exome

AF:

0.000389

Gnomad SAS exome

AF:

0.0109

Gnomad FIN exome

AF:

0.00213

Gnomad NFE exome

AF:

0.00844

Gnomad OTH exome

AF:

0.0208

GnomAD4 exome

AF:

0.0141

AC:

20647

AN:

1461880

Hom.:

646

Cov.:

AF XY:

0.0135

AC XY:

9805

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.0483

Gnomad4 AMR exome

AF:

0.141

Gnomad4 ASJ exome

AF:

0.00505

Gnomad4 EAS exome

AF:

0.000504

Gnomad4 SAS exome

AF:

0.0121

Gnomad4 FIN exome

AF:

0.00266

Gnomad4 NFE exome

AF:

0.00939

Gnomad4 OTH exome

AF:

0.0148

GnomAD4 genome

AF:

0.0273

AC:

4162

AN:

152332

Hom.:

122

Cov.:

AF XY:

0.0277

AC XY:

2066

AN XY:

74498

show subpopulations

Gnomad4 AFR

AF:

0.0473

Gnomad4 AMR

AF:

0.0930

Gnomad4 ASJ

AF:

0.00375

Gnomad4 EAS

AF:

0.00154

Gnomad4 SAS

AF:

0.00870

Gnomad4 FIN

AF:

0.00160

Gnomad4 NFE

AF:

0.00910

Gnomad4 OTH

AF:

0.0223

Alfa

AF:

0.0135

Hom.:

Bravo

AF:

0.0360

TwinsUK

AF:

0.0113

AC:

ALSPAC

AF:

0.00830

AC:

ESP6500AA

AF:

0.0532

AC:

232

ESP6500EA

AF:

0.00866

AC:

ExAC

AF:

0.0257

AC:

3112

Asia WGS

AF:

0.0240

AC:

AN:

3478

EpiCase

AF:

0.00785

EpiControl

AF:

0.00830

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:19

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Wilson disease

Benign:11

Benign, no assertion criteria provided	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 17, 2012	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
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	Sep 27, 2024	- -
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	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, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 28, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Sep 22, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not specified

Benign:6

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 26, 2013	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 23, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 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	-	- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 06, 2015

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. -

not provided

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.14

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Pathogenic

0.89

D;D;.;.;.;.;.

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.12

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.81

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

MetaRNN

Benign

0.0023

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

MetaSVM

Uncertain

-0.10

MutationAssessor

Benign

-1.2

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

MutationTaster

Benign

1.0

D;D;D;D;D;D;D

PrimateAI

Uncertain

0.62

PROVEAN

Uncertain

-4.3

D;D;D;D;D;.;D

REVEL

Uncertain

0.46

Sift

Benign

0.089

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

Sift4G

Benign

0.32

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

Polyphen

0.044

B;D;B;B;B;B;B

Vest4

0.14

MPC

0.094

ClinPred

0.061

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.30

gMVP

0.79

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