chr13-51944231-G-A

Position:

chr13-51944231-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PM5PP3_ModeratePP5_Very_Strong

The NM_000053.4(ATP7B):c.3121C>T(p.Arg1041Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000143 in 1,613,906 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1041P) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

ATP7B
NM_000053.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:12

Conservation

PhyloP100: 0.491

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 Pathogenic. Variant got 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.935

PP5

Variant 13-51944231-G-A is Pathogenic according to our data. Variant chr13-51944231-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 312384.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51944231-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP7B	NM_000053.4 linkuse as main transcript	c.3121C>T	p.Arg1041Trp	missense_variant	14/21	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.3121C>T	p.Arg1041Trp	missense_variant	14/21	1	NM_000053.4	ENSP00000242839	P1	P35670-1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152098

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000321

AC:

AN:

248998

Hom.:

AF XY:

0.0000443

AC XY:

AN XY:

135292

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000708

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000130

AC:

AN:

1461808

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

727214

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000153

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152098

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74286

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000422

Hom.:

Bravo

AF:

0.0000227

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.0000413

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Wilson disease

Pathogenic:8

Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 13, 2023	This missense variant replaces arginine with tryptophan at codon 1041 of the ATP7B protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant alters a conserved arginine residue in the ATP nucleotide binding domain of the ATP7B protein (a.a. 1032 - 1196), a highly conserved region that is considered to be important for ATP7B protein function (PMID: 35245129; ClinVar). It has been shown that this variant does not substantially affect ATP7B protein function in a yeast study (PMID: 18203200). This variant has been reported in almost twenty individuals affected with autosomal recessive Wilson disease (PMID: 9671269, 10544227, 15024742, 15205742, 15967699, 18855987, 20517649, 20931554, 21610751, 22677543, 23333878, 23518715, 25982861, 27022412). This variant was observed in the compound heterozygous state with a second pathogenic variant in at least six affected individuals and in the homozygous state in at least five affected individuals (PMID: 10544227, 15205742, 18855987, 20517649, 21610751, 23518715, 25982861), indicating that this variant contributes to disease. This variant has been identified in 8/248998 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 27, 2023	This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 1041 of the ATP7B protein (p.Arg1041Trp). This variant is present in population databases (rs746485916, gnomAD 0.007%). This missense change has been observed in individual(s) with Wilson disease (PMID: 10544227, 15024742, 15967699, 18855987, 20931554, 21610751, 22677543, 25982861, 27022412; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 312384). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ATP7B protein function with a negative predictive value of 80%. Experimental studies have shown that this missense change does not substantially affect ATP7B function (PMID: 18203200). This variant disrupts the p.Arg1041 amino acid residue in ATP7B. Other variant(s) that disrupt this residue have been observed in individuals with ATP7B-related conditions (PMID: 10194254), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, no assertion criteria provided	clinical testing	Counsyl	Mar 30, 2017	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	Across a selection of the available literature, the ATP7B c.3121C>T (p.Arg1041Trp) missense variant has been identified in a compound heterozygous state in four patients with Wilson disease, including two siblings (Loudianos et al. 1998; Loudianos et al. 1999; Deguti et al. 2004; Kucinskas et al. 2008). Simsek Papur et al. (2013) and Guggilla et al. (2015) also identified the p.Arg1041Trp variant in four alleles in a cohort of affected individuals where zygosity was not stated. Coffey et al. (2013) reported the p.Arg1041Trp variant in a heterozygous state in one of 5,162 controls and it is reported at a frequency of 0.00008 in the European (non-Finnish) population of the Exome Aggregation Consortium. Experiments in yeast revealed that the p.Arg1041Trp variant was able to complement copper transport function, however the evidence is limited as other aspects of protein function were not evaluated (Hsi et al. 2008). Based on the available evidence, the p.Arg1041Trp variant is classified as likely pathogenic for Wilson disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 04, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 26, 2024	- -

not provided

Pathogenic:3

Likely pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 17, 2023	PP3, PP4, PM2, PM3, PM5 -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 19, 2023	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 9671269, 31589614, 24253677, 18203200, 22692182, 27022412, 25982861, 31746411, 29930488, 23518715, 21610751, 34400371, 15967699, 15024742, 20931554, 22677543, 23333878, 18855987, 36360177, 33640437, 32770663, 34470610) -
Pathogenic, criteria provided, single submitter	clinical testing	Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	Aug 29, 2022	PM3, PS3, PP3, PS4, PM2_SUP -

ATP7B-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 12, 2024

The ATP7B c.3121C>T variant is predicted to result in the amino acid substitution p.Arg1041Trp. This variant was reported in large cohorts of individuals with Wilson disease (see, for example, Loudianos et al. 1998. PubMed ID: 9671269; Squitti et al. 2013. PubMed ID: 24253677; Guggilla et al. 2015. PubMed ID: 25982861; Couchonnal et al. 2021. PubMed ID: 34400371; Table S4, Zhang et al. 2022. PubMed ID: 35220961; Bost et al. 2012. PubMed ID: 22677543; Wan et al. 2010. PubMed ID: 20931554; Vrabelova et al. 2005. PubMed ID: 15967699; Deguti et al. 2004. PubMed ID: 15024742). This variant is reported in 0.0071% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.36

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.97

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

Eigen

Uncertain

0.24

Eigen_PC

Benign

0.12

FATHMM_MKL

Uncertain

0.86

LIST_S2

Pathogenic

0.98

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

M_CAP

Pathogenic

0.71

MetaRNN

Pathogenic

0.94

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

MetaSVM

Pathogenic

0.80

MutationAssessor

Benign

2.0

M;.;.;.;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D;N

PrimateAI

Uncertain

0.57

PROVEAN

Pathogenic

-6.2

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

REVEL

Pathogenic

0.83

Sift

Uncertain

0.0010

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

Sift4G

Uncertain

0.0020

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

Polyphen

1.0

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

Vest4

0.70

MVP

0.99

MPC

0.38

ClinPred

0.91

GERP RS

1.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.80

gMVP

0.91

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