13-51975122-A-G

Position:

chr13-51975122-A-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4_StrongBS2_Supporting

The NM_000053.4(ATP7B):c.98T>C(p.Met33Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000857 in 1,614,266 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00089 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00085 ( 2 hom. )

Consequence

ATP7B
NM_000053.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:14B:2

Conservation

PhyloP100: 2.77

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:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.029246747).

BS2

High Homozygotes in GnomAdExome4 at 2 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ATP7B	NM_000053.4 linkuse as main transcript	c.98T>C	p.Met33Thr	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.98T>C	p.Met33Thr	missense_variant	2/21	1	NM_000053.4	ENSP00000242839	P1	P35670-1

Frequencies

GnomAD3 genomes

AF:

0.000887

AC:

135

AN:

152260

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000265

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00281

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000282

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00104

Gnomad OTH

AF:

0.00335

GnomAD3 exomes

AF:

0.000641

AC:

160

AN:

249458

Hom.:

AF XY:

0.000650

AC XY:

AN XY:

135346

show subpopulations

Gnomad AFR exome

AF:

0.000258

Gnomad AMR exome

AF:

0.00110

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000928

Gnomad NFE exome

AF:

0.000954

Gnomad OTH exome

AF:

0.00116

GnomAD4 exome

AF:

0.000854

AC:

1249

AN:

1461888

Hom.:

Cov.:

AF XY:

0.000866

AC XY:

630

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.000358

Gnomad4 AMR exome

AF:

0.00152

Gnomad4 ASJ exome

AF:

0.000153

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000936

Gnomad4 NFE exome

AF:

0.000998

Gnomad4 OTH exome

AF:

0.000811

GnomAD4 genome

AF:

0.000886

AC:

135

AN:

152378

Hom.:

Cov.:

AF XY:

0.000805

AC XY:

AN XY:

74514

show subpopulations

Gnomad4 AFR

AF:

0.000264

Gnomad4 AMR

AF:

0.00281

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000282

Gnomad4 NFE

AF:

0.00104

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.00102

Hom.:

Bravo

AF:

0.00146

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.000524

AC:

ESP6500EA

AF:

0.000972

AC:

ExAC

AF:

0.000596

AC:

EpiCase

AF:

0.00109

EpiControl

AF:

0.00136

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:14Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:5Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 11, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 12, 2023	PM2 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 22, 2024	Observed with a missense variant in a patient with late-onset Wilson disease, but it is not known whether the variants occurred on the same (in cis) or on different (in trans) chromosomes (PMID: 36632541); In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23518715, 24253677, 34620762, 36632541) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	ATP7B: PM2, PM3:Supporting -
Uncertain significance, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Wilson disease

Uncertain:6

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 12, 2020	The ATP7B c.98T>C; p.Met33Thr variant (rs184868522), to our knowledge, is not reported in an individual affected with Wilson disease, but has been described in an unaffected individual (Squitti 2019). The variant is listed in the ClinVar database (Variation ID: 35736) and is reported in the general population with an overall allele frequency of 0.06% (180/280858 alleles) in the Genome Aggregation Database. The methionine at codon 33 is weakly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is tolerated. Due to limited information, the clinical significance of the p.Met33Thr variant is uncertain at this time. References: Squitti R et al. A case of a mild Wolfram Syndrome with concomitant ATP7B mutation. CellR4. 2019; 7: e2735. -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	This missense variant replaces methionine with threonine at codon 33 of the ATP7B protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in an individual with low levels of copper and ceruloplasmin (PMID: 24253677). This variant has been identified in 180/280858 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 15, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 01, 2022	This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 33 of the ATP7B protein (p.Met33Thr). This variant is present in population databases (rs184868522, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with Wilson disease (PMID: 23518715). ClinVar contains an entry for this variant (Variation ID: 35736). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 06, 2024

Variant summary: ATP7B c.98T>C (p.Met33Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00064 in 251146 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in ATP7B causing Wilson Disease (0.00064 vs 0.0054), allowing no conclusion about variant significance. c.98T>C has been reported in the literature as a presumed compound heterozygous genotype in at-least one individual affected with late onset Wilson Disease (example, Barros de Oliveira_2022). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 36632541, 23518715, 24253677, 35637795). ClinVar contains an entry for this variant (Variation ID: 35736). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 10, 2017

- -

ATP7B-related disorder

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 13, 2023

The ATP7B c.98T>C variant is predicted to result in the amino acid substitution p.Met33Thr. This variant was previously reported in a clinically asymptomatic individual with decreased serum copper and ceruloplasmin levels but increased urinary copper after a D-penicillamine challenge test (Squitti et al. 2019. PubMed ID: 33869661). The variant was also seen in an elderly man diagnosed with late-onset Wilson disease who also carried a second ATP7B variant of uncertain significance (Barros de Oliveira Sá et al. 2022. PubMed ID: 36632541).This variant is reported in 0.11% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/13-52549258-A-G). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.099

BayesDel_noAF

Uncertain

0.080

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.52

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

Eigen

Benign

0.10

Eigen_PC

Benign

0.21

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.75

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

M_CAP

Pathogenic

0.48

MetaRNN

Benign

0.029

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

MetaSVM

Uncertain

0.45

MutationAssessor

Benign

2.0

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

MutationTaster

Benign

1.0

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

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-1.6

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

REVEL

Uncertain

0.60

Sift

Benign

0.13

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

Sift4G

Benign

0.073

T;T;D;T;T;T;T

Polyphen

0.025

B;P;D;P;D;B;P

Vest4

0.36

MVP

0.97

MPC

0.067

ClinPred

0.031

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.15

gMVP

0.63

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