rs1038582488

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM1PM2PP2PP3_ModeratePP5_Very_Strong

The NM_000053.4(ATP7B):c.2939G>A(p.Cys980Tyr) 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 1,614,028 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 (★★). Synonymous variant affecting the same amino acid position (i.e. C980C) has been classified as Likely benign.

Frequency

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

Exomes 𝑓: 0.000015 ( 0 hom. )

Consequence

ATP7B
NM_000053.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7U:1

Conservation

PhyloP100: 1.89

Publications

6 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 15 ACMG points.

PM1

In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 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, 0.924

PP5

Variant 13-51946405-C-T is Pathogenic according to our data. Variant chr13-51946405-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 556603.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ATP7B	NM_000053.4 link	c.2939G>A	p.Cys980Tyr	missense_variant	Exon 13 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.2939G>A	p.Cys980Tyr	missense_variant	Exon 13 of 21	1	NM_000053.4	ENSP00000242839.5		P35670-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152250

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:

249386

AF XY:

0.00000739

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:

0.00000884

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000151

AC:

AN:

1461778

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727184

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44720

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:

86232

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5692

European-Non Finnish (NFE)

AF:

0.0000189

AC:

AN:

1112012

Other (OTH)

AF:

0.0000166

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

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:

152250

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74390

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

41468

American (AMR)

AF:

0.00

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4838

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68044

Other (OTH)

AF:

0.00

AC:

AN:

2092

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.0000186

Hom.:

Bravo

AF:

0.0000113

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Wilson disease

Pathogenic:6Uncertain:1

Feb 09, 2018

Counsyl

Significance:Likely pathogenic

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. -

Apr 01, 2022

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The ATP7B c.2939G>A; p.Cys980Tyr variant (rs1038582488) is reported in the literature in multiple individuals affected with Wilson disease, often found with a second pathogenic variant (Li 2013, Mak 2008, Xiao 2021). This variant is reported in ClinVar (Variation ID: 556603) and is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. Additionally, other variants at this codon (c.2939G>T, p.Cys980Phe; c.2938T>C, p.Cys980Arg) have been reported in individuals with Wilson disease (Li 2019, Li 2013). The cysteine at codon 980 is weakly conserved, but computational analyses predict that this variant is deleterious (REVEL: 0.773). Based on available information, this variant is considered to be likely pathogenic. References: Li X et al. Clinical features and mutational analysis in 114 young children with Wilson disease from South China. Am J Med Genet A. 2019 Aug;179(8):1451-1458. PMID: 31172689. Li K et al. Mutational analysis of ATP7B in north Chinese patients with Wilson disease. J Hum Genet. 2013 Feb;58(2):67-72. PMID: 23235335. Mak CM et al. Mutational analysis of 65 Wilson disease patients in Hong Kong Chinese: identification of 17 novel mutations and its genetic heterogeneity. J Hum Genet. 2008;53(1):55-63. PMID: 18034201. Xiao Z et al. Molecular analysis of 53 Chinese families with Wilson's disease: Six novel mutations identified. Mol Genet Genomic Med. 2021 Sep;9(9):e1735. PMID: 34324271. -

Jul 03, 2023

Baylor Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 03, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces cysteine, which is neutral and slightly polar, with tyrosine, which is neutral and polar, at codon 980 of the ATP7B protein (p.Cys980Tyr). This variant is present in population databases (no rsID available, gnomAD 0.0009%). This missense change has been observed in individual(s) with Wilson disease (PMID: 21796144, 24146181, 34324271). ClinVar contains an entry for this variant (Variation ID: 556603). 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%. For these reasons, this variant has been classified as Pathogenic. -

Nov 02, 2022

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

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: ATP7B c.2939G>A (p.Cys980Tyr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 249386 control chromosomes (gnomAD). c.2939G>A has been reported in the literature in multiple individuals affected with Wilson Disease (e.g. Wang_2011, Li_2013, Hui_2013, Wang_2018, Xiao_2021, Poon_2016, Mak_2008). These data indicate that the variant is very likely to be associated with disease. One ClinVar submitter has assessed the variant since 2014: the variant was classified as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Apr 10, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 15, 2023

All of Us Research Program, National Institutes of Health

Significance:Uncertain significance

Review Status:flagged submission

Collection Method:clinical testing

- -

ATP7B-related disorder

Pathogenic:1

Nov 10, 2022

PreventionGenetics, part of Exact Sciences

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The ATP7B c.2939G>A variant is predicted to result in the amino acid substitution p.Cys980Tyr. This variant was reported along with a known pathogenic variant (c.2333G>T, p.Arg778Leu) in an individual with Wilson disease (Fang et al. 2021. PubMed ID: 34002136). It has also been reported in other Wilson disease patients, although without additional functional or genetic evidence (for example, see Mak et al. 2007. PubMed ID: 18034201; Li et al. 2013. PubMed ID: 23235335; Poon et al. 2016. PubMed ID: 26483271; Wei et al. 2014. PubMed ID: 25089800). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/13-52520541-C-T). This variant is interpreted as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.39

BayesDel_noAF

Pathogenic

0.32

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Pathogenic

0.91

D;D;.;.;.;.

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Uncertain

0.93

LIST_S2

Pathogenic

0.99

D;D;D;D;D;D

M_CAP

Pathogenic

0.47

MetaRNN

Pathogenic

0.92

D;D;D;D;D;D

MetaSVM

Uncertain

0.64

MutationAssessor

Benign

0.97

L;.;.;.;.;.

PhyloP100

1.9

PrimateAI

Uncertain

0.74

PROVEAN

Pathogenic

-6.0

D;D;D;D;D;.

REVEL

Pathogenic

0.77

Sift

Uncertain

0.0010

D;D;D;D;D;.

Sift4G

Uncertain

0.0050

D;D;D;D;D;D

Polyphen

1.0

D;D;D;B;D;D

Vest4

0.82

MVP

0.97

MPC

0.45

ClinPred

0.99

GERP RS

5.2

Varity_R

0.95

gMVP

0.95

Mutation Taster

=3/97

disease causing (ClinVar)

(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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over