rs72552285

chr13-51961859-C-Achr13-51961859-C-Gchr13-51961859-C-T

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2 PM5 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D642H) has been classified 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:5
• 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 13 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr13-51961859-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 189109.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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/exons	MANE	UniProt
ATP7B	NM_000053.4	c.1924G>T	p.Asp642Tyr	missense_variant	6/21	ENST00000242839.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP7B	ENST00000242839.10	c.1924G>T	p.Asp642Tyr	missense_variant	6/21	1	NM_000053.4	P1

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:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Wilson disease Pathogenic:5

Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 26, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 15, 2023	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. For these reasons, this variant has been classified as Pathogenic. 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 526655). 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. This variant is present in population databases (no rsID available, gnomAD 0.006%). 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). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

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;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;N
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;