chr13-51961859-C-A

Variant names:

• chr13-51961859-C-A
• rs72552285
• NM_000053.4:c.1924G>T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM2 PP3 PP5_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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 5.40

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]

ACMG classification

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
ATP7B	NM_000053.4	c.1924G>T	p.Asp642Tyr	missense_variant	Exon 6 of 21	ENST00000242839.10	NP_000044.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ATP7B	ENST00000242839.10	c.1924G>T	p.Asp642Tyr	missense_variant	Exon 6 of 21	1	NM_000053.4	ENSP00000242839.5

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

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

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

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

Other links and lift over

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