rs775055397

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PM1PM5PP2PP3_StrongPP5_Very_Strong

The NM_000053.4(ATP7B):c.3008C>T(p.Ala1003Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000249 in 1,609,040 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. A1003T) has been classified as Pathogenic.

Frequency

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

Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

ATP7B
NM_000053.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:16

Conservation

PhyloP100: 9.93

Publications

18 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 17 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000053.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chr13-51946337-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 188802.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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, 0.991

PP5

Variant 13-51946336-G-A is Pathogenic according to our data. Variant chr13-51946336-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 188781.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.3008C>T	p.Ala1003Val	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.3008C>T	p.Ala1003Val	missense_variant	Exon 13 of 21	1	NM_000053.4	ENSP00000242839.5		P35670-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152252

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:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000333

AC:

AN:

240390

AF XY:

0.0000535

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000268

AC:

AN:

1456788

Hom.:

Cov.:

AF XY:

0.0000345

AC XY:

AN XY:

724330

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33400

American (AMR)

AF:

0.00

AC:

AN:

44144

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26018

East Asian (EAS)

AF:

0.00

AC:

AN:

39594

South Asian (SAS)

AF:

0.000257

AC:

AN:

85494

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53058

Middle Eastern (MID)

AF:

0.000210

AC:

AN:

4766

European-Non Finnish (NFE)

AF:

0.00000991

AC:

AN:

1110192

Other (OTH)

AF:

0.0000832

AC:

AN:

60122

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152252

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74378

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:

41472

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:

5192

South Asian (SAS)

AF:

0.000207

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68050

Other (OTH)

AF:

0.00

AC:

AN:

2094

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000189

Hom.:

ExAC

AF:

0.0000662

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:16

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Wilson disease

Pathogenic:14

Oct 11, 2020

Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 22, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The observed missense c.3008C>Tp.Ala1003Val variant in ATP7B gene has been previously reported in homozygous and compound heterozygous states in multiple individuals affected with Wilson disease Singh N, et al., 2019; Santhosh S, et al., 2006 . The variant p.Ala1003Val is present with allele frequency of 0.003% in gnomAD exomes. This variant has been submitted to ClinVar as Likely Pathogenic / Pathogenic multiple submissions. Multiple lines of computational evidences SIFT- Damaging, Polyphen - Probably damaging, MutationTaster - Disease causing predict a damaging effect on protein structure and function for this variant. The reference amino acid change at this position on ATP7B gene is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Ala at position 1003 is changed to a Val changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. -

Aug 10, 2021

Genome-Nilou Lab

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 11, 2020

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.Ala1003Val variant in ATP7B has been reported in several individuals with Wilson disease, including at least 2 homozygotes and 1 compound heterozygote; however, in the majority of studies, allelic data (cis/trans, homozygous or compound heterozygous state) was not reported (Mukherjee 2014, Simsek 2013, Guggilla 2015, Santhosh 2006, Loudianos 1999, Kumari 2018, Gomes 2016, Gupta 2007, Coffey 2013). This variant has also been identified in 0.02% (8/29742) of South Asian chromosomes by gnomAD (http://gnomad.broadinstitute.org). A pathogenic variant affecting the same amino acid position, p.Ala1003Thr, has been previously reported in many individuals with Wilson disease. Computational prediction tools and conservation analysis suggest that this variant may impact the protein. In summary, although additional studies are required to fully establish its clinical significance, this variant meets criteria to be classified as likely pathogenic for autosomal Wilson disease. ACMG/AMP criteria applied: PM2, PM5, PP3, PP4, PM3_Supporting. -

Aug 11, 2025

Centre for Inherited Metabolic Diseases, Karolinska University Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Used criteria: PS1, PS4, PM2, PP3. -

May 14, 2014

Counsyl

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

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. -

Feb 06, 2025

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 25, 2023

Institute of Human Genetics, University of Leipzig Medical Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Criteria applied: PM3_VSTR,PS4_MOD,PP3; Identified as compund heterozygous with NM_000053.4:c.2906G>A -

Dec 09, 2019

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.3008C>T (p.Ala1003Val) 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 3.3e-05 in 240390 control chromosomes (gnomAD). c.3008C>T has been reported in the literature in multiple individuals affected with Wilson Disease (e.g. Loudianos_1999, Coffey_2013, Guggilla_2015). These data indicate that the variant is very likely to be associated with disease. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. -

Mar 21, 2024

Baylor Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1003 of the ATP7B protein (p.Ala1003Val). This variant is present in population databases (rs775055397, gnomAD 0.03%). This missense change has been observed in individual(s) with Wilson disease (PMID: 10544227, 17264425, 31059521). ClinVar contains an entry for this variant (Variation ID: 188781). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt ATP7B protein function with a positive predictive value of 80%. This variant disrupts the p.Ala1003 amino acid residue in ATP7B. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12885331, 21610751, 26799313; internal data). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Mar 25, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 22, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 05, 2018

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Pathogenic:1

Sep 04, 2020

Mayo Clinic Laboratories, Mayo Clinic

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

PS4_moderate, PM2, PM5, PP4 -

Abnormality of metabolism/homeostasis

Pathogenic:1

Jul 10, 2021

Kariminejad - Najmabadi Pathology & Genetics Center

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.84

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.46

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.93

D;D;.;.;.;.

Eigen

Pathogenic

0.71

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

D;D;D;D;D;D

M_CAP

Pathogenic

0.74

MetaRNN

Pathogenic

0.99

D;D;D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Uncertain

2.9

M;.;.;.;.;.

PhyloP100

9.9

PrimateAI

Uncertain

0.72

PROVEAN

Uncertain

-3.6

D;D;D;D;D;.

REVEL

Pathogenic

0.87

Sift

Uncertain

0.0010

D;D;D;D;D;.

Sift4G

Uncertain

0.0020

D;D;D;D;D;D

Polyphen

1.0

D;D;D;B;P;D

Vest4

0.95

MutPred

0.98

Loss of helix (P = 0.2022);.;.;.;.;.;

MVP

0.92

MPC

0.38

ClinPred

0.92

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.91

gMVP

0.95

Mutation Taster

=0/100

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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rs775055397

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