GeneBe

rs72552285

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2PP3PP5_Very_Strong

The NM_000053.4(ATP7B):​c.1924G>T​(p.Asp642Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.0000041 in 1,461,752 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 (★★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

ATP7B
NM_000053.4 missense

Scores

11
5
3

Clinical Significance

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

Conservation

PhyloP100: 5.40
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 11 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.803
PP5
Variant 13-51961859-C-A is Pathogenic according to our data. Variant chr13-51961859-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 526655.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
ATP7BNM_000053.4 linkc.1924G>T p.Asp642Tyr missense_variant Exon 6 of 21 ENST00000242839.10 NP_000044.2 P35670-1B7ZLR4A0A024RDX3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ATP7BENST00000242839.10 linkc.1924G>T p.Asp642Tyr missense_variant Exon 6 of 21 1 NM_000053.4 ENSP00000242839.5 P35670-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000801
AC:
2
AN:
249582
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135408
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:
0.0000654
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000410
AC:
6
AN:
1461752
Hom.:
0
Cov.:
31
AF XY:
0.00000413
AC XY:
3
AN XY:
727182
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000696
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Wilson disease Pathogenic:7
Mar 04, 2024
All of Us Research Program, National Institutes of Health
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Functional studies suggest that this variant results in a deleterious effect on the protein (PMID: 30120852). This variant is present in 2/249582 total alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/). This variant was detected in multiple individuals affected with Wilson disease as homozygous or as compound heterozygous (in trans) with a likely pathogenic or pathogenic variant, which is consistent with autosomal recessive inheritance (PMID: 30120852, 29540233, 36112267). A different missense substitution at this amino acid residue has been previously reported in individuals with disease and classified as pathogenic which supports the functional importance of this position. (PMID: 8203200, 21610751, 21682854, 24706876) .This variant has been reported to co-segregate with disease in one family (PMID: 29540233). This variant is predicted to be deleterious by in silico analysis. -

Feb 05, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with tyrosine, which is neutral and polar, at codon 642 of the ATP7B protein (p.Asp642Tyr). This variant is present in population databases (no rsID available, gnomAD 0.006%). This missense change has been observed in individual(s) with Wilson's disease (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: 526655). 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%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. This variant disrupts the p.Asp642 amino acid residue in ATP7B. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 8203200, 21610751, 21682854, 24706876). 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. -

Aug 10, 2021
Genome-Nilou Lab
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Sep 25, 2024
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.1924G>T (p.Asp642Tyr) 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 8e-06 in 249582 control chromosomes. c.1924G>T has been reported in the literature in at least three homozygous siblings affected with Wilson Disease (e.g., Kumari_2018). These data indicate that the variant is very likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, indicating this variant reduces cell viability and affects the copper transport capability of ATP7B (Kumari_2018). The following publication have been ascertained in the context of this evaluation (PMID: 30120852). ClinVar contains an entry for this variant (Variation ID: 526655). Based on the evidence outlined above, the variant was classified as pathogenic. -

Oct 31, 2018
Fulgent Genetics, Fulgent Genetics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 18, 2023
Baylor Genetics
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Neuberg Centre For Genomic Medicine, NCGM
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The variant c.1924G>T (p.Asp642Tyr) in ATP7B gene has been reported in homozygous or compound heterozygous state in individuals affected with wilson disease (Kitamura K et al). This variant has been observed on the opposite chromosome (in trans) from a pathogenic variant in an individual affected with Wilson's disease. This finding is consistent with autosomal recessive inheritance, and suggests that this variant contributes to disease. A different missense substitution at this codon (p.Asp642His) has been determined to be pathogenic (Kitamura K et al). This suggests that the aspartic acid residue is critical for ATP7B protein function and that other missense substitutions at this position may also be pathogenic. The p.Asp642Tyr variant is reported with the allele frequency of 0.0008013% in gnomAD and is novel (not in any individuals) in 1000 Genomes. This variant has been reported to the ClinVar database as Pathogenic/ Likely Pathogenic. The amino acid Asp at position 642 is changed to a Tyr changing protein sequence and it might alter its composition and physico-chemical properties. The variant is predicted to be damaging by both SIFT and PolyPhen2. The residue is conserved across species. The amino acid change p.Asp642Tyr in ATP7B is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.33
BayesDel_addAF
Uncertain
0.16
D
BayesDel_noAF
Pathogenic
0.17
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.83
D;T;.;.;.
Eigen
Pathogenic
0.76
Eigen_PC
Pathogenic
0.73
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Benign
0.77
T;T;T;T;T
M_CAP
Pathogenic
0.30
D
MetaRNN
Pathogenic
0.80
D;D;D;D;D
MetaSVM
Pathogenic
0.94
D
MutationAssessor
Pathogenic
3.9
H;.;.;.;.
PrimateAI
Uncertain
0.56
T
PROVEAN
Pathogenic
-7.4
D;D;D;.;D
REVEL
Pathogenic
0.76
Sift
Uncertain
0.0010
D;D;D;.;D
Sift4G
Uncertain
0.0030
D;D;D;D;D
Polyphen
1.0
D;D;B;D;D
Vest4
0.75
MutPred
0.55
Loss of disorder (P = 0.0165);Loss of disorder (P = 0.0165);.;Loss of disorder (P = 0.0165);Loss of disorder (P = 0.0165);
MVP
0.92
MPC
0.38
ClinPred
1.0
D
GERP RS
5.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.86
gMVP
0.84

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.26
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.26
Position offset: -22

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.

Other links and lift over

dbSNP: rs72552285; hg19: chr13-52535995; COSMIC: COSV54435117; COSMIC: COSV54435117; API