rs786204653

chr13-51941120-C-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000053.4(ATP7B):c.3517G>A(p.Glu1173Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,614,036 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. E1173G) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: ATP7B NM_000053.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 7.86

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 18 ACMG points.

• PM1: In a hotspot region, there are 4 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.978
• PP5: Variant 13-51941120-C-T is Pathogenic according to our data. Variant chr13-51941120-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 189050.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.3517G>A	p.Glu1173Lys	missense_variant	16/21	ENST00000242839.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP7B	ENST00000242839.10	c.3517G>A	p.Glu1173Lys	missense_variant	16/21	1	NM_000053.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152148 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 249590 Hom.: 0 AF XY: 0.0000222 AC XY: 3 AN XY: 135408

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461888 Hom.: 0 Cov.: 30 AF XY: 0.00000550 AC XY: 4 AN XY: 727244

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152148 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74322

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000688 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.00000827 AC: 1

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Wilson disease Pathogenic:10

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Apr 13, 2017	Variant summary: The ATP7B c.3517G>A (p.Glu1173Lys) variant involves the alteration of a conserved nucleotide, resulting in a missense substitution. The variant lies within the HAD-like domain and P-type ATPase, cytoplasmic domain N (InterPro). 4/5 in silico tools predict a damaging outcome for this variant. This variant was found in the large control database ExAC and control cohorts in the literature at a frequency of 0.0000082 (1/121248 control chromosomes), which does not exceed the estimated maximal expected allele frequency of a pathogenic ATP7B variant (0.0054006). Multiple publications have reported the variant in Wilson disease patients. One study that provided familial genotyping data to confirm inheritance of the variant of interest along with a second pathogenic allele (Lee_TP7B_JHG_2000). One clinical diagnostic laboratory and several reputable databases have classified this variant as likely pathogenic or pathogenic. Taken together, this variant is classified as pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Aug 16, 2018	The ATP7B c.3517G>A (p.Glu1173Lys) missense variant has been reported in seven studies in which it is found in a compound heterozygous state in at least seven patients and in a heterozygous state in at least eight patients, all with Wilson disease (Loudianos et al. 1999; Lee et al. 2000; Chappuis et al. 2007; Geng et al. 2013; Gu et al. 2013; Cheng et al. 2014; Dong et al. 2016). In at least one family in which the patient was compound heterozygous for the p.Glu1173Lys variant and a missense variant, the unaffected sister and father were identified to be heterozygous for the p.Glu1173Lys variant while the unaffected mother was heterozygous for the other missense variant. This variant was absent from at least 77 controls and is reported at a frequency of 0.000012 in the total population from the Genome Aggregation Database. Based on the evidence, the p.Glu1173Lys variant is classified as pathogenic for Wilson disease. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Nov 06, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 12, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Feb 05, 2024	This missense variant replaces glutamic acid with lysine at codon 1173 of the ATP7B protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). This variant alters a conserved glutamic acid residue in the N domain of the ATP7B protein (a.a. 1032 - 1196), a highly conserved region that is considered to be important for ATP7B protein function (PMID: 35245129; ClinVar). To our knowledge, functional studies have not been reported for this variant. This variant has been observed in individuals affected with autosomal recessive Wilson disease (PMID: 10544227, 11043508, 11405812, 11775208, 14986826, 17317524, 23275100, 23843956, 24718822, 27022412, 30702195), including in 1 individual in the homozygous state (PMID: 27022412) and in 10 individuals in the compound heterozygous state or in unknown phase with a second pathogenic variant in the ATP7B gene (PMID: 10544227, 11043508, 11775208, 17317524, 23275100, 23843956, 24718822, 30702195). This variant has been identified in 3/249590 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 22, 2023	This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 1173 of the ATP7B protein (p.Glu1173Lys). This variant is present in population databases (rs756029120, gnomAD 0.01%). This missense change has been observed in individual(s) with Wilson disease (PMID: 10544227, 17680703, 23275100, 23843956, 27022412; 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: 189050). 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%. Experimental studies have shown that this missense change affects ATP7B function (PMID: 20333758). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jan 04, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 31, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.50
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D;D;.;.;.;.;.
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;D;D;D;D;D
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Benign	1.5	L;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-3.5	D;D;D;D;D;.;D
REVEL	Pathogenic	0.92
Sift	Uncertain	0.0020	D;D;D;D;D;.;D
Sift4G	Uncertain	0.0020	D;D;D;D;D;D;D
Polyphen		0.98	D;D;D;D;D;D;D
Vest4		0.91
MutPred		0.83		Gain of ubiquitination at E1173 (P = 0.0146);.;.;.;.;.;.;
MVP		1.0
MPC		0.39
ClinPred		0.99	D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.94
gMVP		0.92

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

LitVar

Other links and lift over

dbSNP: rs756029120; hg19: chr13-52515256; COSMIC: COSV54436876; COSMIC: COSV54436876;