rs374628199

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1PM2PP2PP3_StrongPP5

The NM_000053.4(ATP7B):c.3716T>G(p.Val1239Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000013 in 1,614,106 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1239F) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

ATP7B
NM_000053.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7U:3

Conservation

PhyloP100: 7.51

Publications

5 publications found

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 Gene-Disease associations (from GenCC):

Wilson disease
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Genomics England PanelApp, Orphanet, Labcorp Genetics (formerly Invitae)

ATP7B links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 12 uncertain in NM_000053.4

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 198 curated pathogenic missense variants (we use a threshold of 10). The gene has 32 curated benign missense variants. Gene score misZ: -0.88091 (below the threshold of 3.09). Trascript score misZ: 0.82063 (below the threshold of 3.09). GenCC associations: The gene is linked to Wilson disease.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.939

PP5

Variant 13-51937663-A-C is Pathogenic according to our data. Variant chr13-51937663-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 456557.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP7B	NM_000053.4 link	c.3716T>G	p.Val1239Gly	missense_variant	Exon 18 of 21	ENST00000242839.10	NP_000044.2	P35670-1B7ZLR4A0A024RDX3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP7B	ENST00000242839.10 link	c.3716T>G	p.Val1239Gly	missense_variant	Exon 18 of 21	1	NM_000053.4	ENSP00000242839.5		P35670-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152222

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000401

AC:

AN:

249548

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000883

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000137

AC:

AN:

1461884

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727244

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000180

AC:

AN:

1112010

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152222

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74360

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41462

American (AMR)

AF:

0.00

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68038

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000757

Hom.:

Bravo

AF:

0.00000378

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000119

AC:

ExAC

AF:

0.00000827

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:7Uncertain:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Wilson disease

Pathogenic:5Uncertain:3

Sep 16, 2020

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 09, 2024

All of Us Research Program, National Institutes of Health

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces valine with glycine at codon 1239 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 valine residue in the phosphorylation domain of the ATP7B protein (a.a. 1004 - 1031, 1197 - 1312), a highly conserved region that is considered to be important for ATP7B protein function (PMID: 35245129; ClinVar). A functional study in yeast has shown that this variant results in the lack of ATP7B protein expression and inability to complement ccc2 deficiency (PMID: 20333758). This variant has been observed in individuals affected with autosomal recessive Wilson disease (PMID: 10502777, 23518715, 34470610), including at least one individual in the compound heterozygous state with a second pathogenic ATP7B variant (PMID: 23518715). This variant has been identified in 1/249548 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

May 22, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces valine, which is neutral and non-polar, with glycine, which is neutral and non-polar, at codon 1239 of the ATP7B protein (p.Val1239Gly). This variant is present in population databases (rs374628199, gnomAD 0.0009%). This missense change has been observed in individual(s) with clinical features of Wilson disease (PMID: 10502777, 23518715, 34470610; Invitae). ClinVar contains an entry for this variant (Variation ID: 456557). 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 expected to disrupt ATP7B protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects ATP7B function (PMID: 22692182). This variant disrupts the p.Val1239 amino acid residue in ATP7B. Other variant(s) that disrupt this residue have been observed in individuals with ATP7B-related conditions (PMID: 35220961), which suggests that this may be a clinically significant amino acid residue. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Aug 10, 2021

Genome-Nilou Lab

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 26, 2017

Counsyl

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Jul 05, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The ATP7B c.3716T>G; p.Val1239Gly variant (rs374628199, ClinVar Variation ID 456557) is reported in the literature in individuals affected with Wilson disease (Coffey 2013, Curtis 1999, Li 2021). This variant is only observed on one allele in the Genome Aggregation Database (v2.1.1), indicating it is not a common polymorphism. Computational analyses predict that this variant is deleterious (REVEL: 0.962), and in vitro functional analyses demonstrate low protein expression and a deleterious effect on protein function (Luoma 2010). Additionally, another variant at this codon (c.3715G>T; p.Val1239Phe) has been reported in individuals affected with Wilson disease (Li 2021, Zhang 2022). Based on available information, the p.Val1239Gly variant is considered to be likely pathogenic. References: Coffey AJ et al. A genetic study of Wilson's disease in the United Kingdom. Brain. 2013 May;136(Pt 5):1476-87. PMID: 23518715. Curtis D et al. A study of Wilson disease mutations in Britain. Hum Mutat. 1999;14(4):304-11. PMID: 10502777. Li M et al. Mutation analysis of the ATP7B gene and genotype-phenotype correlation in Chinese patients with Wilson disease. BMC Gastroenterol. 2021 Sep 1;21(1):339. PMID: 34470610. Luoma LM et al. Functional analysis of mutations in the ATP loop of the Wilson disease copper transporter, ATP7B. Hum Mutat. 2010 May;31(5):569-77. PMID: 20333758. Zhang S et al. Clinical and genetic characterization of a large cohort of patients with Wilson's disease in China. Transl Neurodegener. 2022 Feb 28;11(1):13. PMID: 35220961. -

Apr 11, 2024

Color Diagnostics, LLC DBA Color Health

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense variant replaces valine with glycine at codon 1239 of the ATP7B protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function. This variant alters a conserved valine residue in the phosphorylation domain of the ATP7B protein (a.a. 1004 - 1031, 1197 - 1312), a highly conserved region that is considered to be important for ATP7B protein function (PMID: 35245129; ClinVar). A functional study in yeast has shown that this variant results in the lack of ATP7B protein expression and inability to complement ccc2 deficiency (PMID: 20333758). This variant has been observed in individuals affected with autosomal recessive Wilson disease (PMID: 10502777, 23518715, 34470610), including at least one individual in the compound heterozygous state with a second pathogenic ATP7B variant (PMID: 23518715). This variant has been identified in 1/249548 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

Inborn genetic diseases

Pathogenic:1

Mar 22, 2016

Ambry Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.V1239G variant (also known as c.3716T>G), located in coding exon 18 of the ATP7B gene, results from a T to G substitution at nucleotide position 3716. The valine at codon 1239 is replaced by glycine, an amino acid with dissimilar properties. This variant was detected in a British patient with Wilson disease; however, a second alteration was not reported (Curtis D, Hum. Mutat. 1999 ; 14(4):304-11). Functional studies of this alteration showed low protein expression and a deleterious impact on the protein function (Luoma LM, Hum. Mutat. 2010 May; 31(5):569-77). This variant was previously reported in the SNPDatabase as rs374628199. Based on data from the NHLBI Exome Sequencing Project (ESP), the G allele has an overall frequency of approximately 0.01% (1/12418) total alleles studied and 0.01% (1/8380) European American alleles. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

not provided

Pathogenic:1

Sep 30, 2019

Mayo Clinic Laboratories, Mayo Clinic

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PS3, PM2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.82

BayesDel_addAF

Pathogenic

0.56

BayesDel_noAF

Pathogenic

0.57

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.96

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

Eigen

Pathogenic

0.76

Eigen_PC

Pathogenic

0.68

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.97

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

M_CAP

Pathogenic

0.89

MetaRNN

Pathogenic

0.94

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

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.2

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

PhyloP100

7.5

PrimateAI

Uncertain

0.61

PROVEAN

Pathogenic

-6.4

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

REVEL

Pathogenic

0.96

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0

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

Polyphen

1.0

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

Vest4

0.81

MVP

0.99

MPC

0.42

ClinPred

0.99

GERP RS

4.7

Varity_R

0.97

gMVP

0.96

Mutation Taster

=0/100

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over