rs786204419

chr13-51949723-G-A

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1 PM2 PP3 PP5_Very_Strong

The NM_000053.4(ATP7B):c.2804C>T(p.Thr935Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000434 in 1,613,884 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. T935T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000044 (1 hom.)
• Consequence: ATP7B NM_000053.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:13
• Conservation: PhyloP100: 9.94

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.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 4 uncertain in NM_000053.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.783
• PP5: Variant 13-51949723-G-A is Pathogenic according to our data. Variant chr13-51949723-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 188713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51949723-G-A is described in Lovd as [Likely_pathogenic]. Variant chr13-51949723-G-A is described in Lovd as [Pathogenic]. Variant chr13-51949723-G-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ATP7B	NM_000053.4	c.2804C>T	p.Thr935Met	missense_variant	12/21	ENST00000242839.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ATP7B	ENST00000242839.10	c.2804C>T	p.Thr935Met	missense_variant	12/21	1	NM_000053.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152108 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000189 AC: 47 AN: 249318 Hom.: 0 AF XY: 0.000185 AC XY: 25 AN XY: 135290

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00250

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000445 AC: 65 AN: 1461776 Hom.: 1 Cov.: 36 AF XY: 0.0000440 AC XY: 32 AN XY: 727188

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000705

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000306

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152108 Hom.: 0 Cov.: 32 AF XY: 0.0000404 AC XY: 3 AN XY: 74282

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000192

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000917 Hom.: 0

Bravo AF: 0.000102

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.000174 AC: 21

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Wilson disease Pathogenic:11

Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Mar 03, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2020	The p.Thr935Met variant in ATP7B has been reported in at least 10 compound heterozygous individuals with clinical features of Wilson disease and is one of the most common variants detected in Asian patients with this disorder (Wu 2001, Gu 2003, and Chen 2014). It has also been reported by other clinical laboratories in ClinVar (Variation ID 188713). This variant has been identified in 0.2% (46/19536) of East Asian chromosomes by gnomAD (https://gnomad.broadinstitute.org/). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. In vitro functional studies support an impact on protein function (Zhu 2015) and computational prediction tools and conservation analyses suggest are consistent with pathogenicity. In summary, this variant meets criteria to be classified as pathogenic for autosomal recessive Wilson disease. ACMG/AMP Criteria applied: PM3_VeryStrong, PP3, PS3_Supporting. -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 12, 2023	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 23, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 21, 2016	Variant summary: The ATP7B c.2804C>T (p.Thr935Met) variant involves the alteration of a conserved nucleotide and is located in the transmembrane 5 domain of the ATP7B protein, known to be associated with copper excretion (ACMG PM1). 5/5 in silico tools predict a damaging outcome for this variant (ACMG PP3). This variant was found in 22/121398 control chromosomes, predominantly observed in the East Asian subpopulation at a frequency of 0.0023218 (20/8614) which could represent carriers of Wilson Disease (ACMG PM2). This variant has been reported in numerous WD patients both as homozygotes and as compound heterozygotes, mainly of East Asian origin (ACMG PM3). A recently published study reported an odds ratio of 77.044 (95% CI 10.716-553.9) for this variant based on Its prevalence in affected individuals as compared to controls (ACMG PS4). In addition, one clinical diagnostic laboratory classified this variant as likely pathogenic. Functional study with stable transfected CHO cell showed variant with comparable level of CuCl2-induced copper overloading of CHO cells. The influence of ATP7B on copper elimination by variant of interest is minimal, and T935M mutation maintained the subcellular localization or trafficking of ATP7B protein. Taken together, even though the functional effect of variant is not obvious, this variant fulfills the criteria required to be classified as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Nov 30, 2023	Participant 844873 has only uninformative additional variants, zygosity needs to be checked. The T935M variant is the third most common ATP7B pathogenic variant identified in the Chinese population, and may be considered a founder mutation (PMID: 33668890). In silico analysis suggest that this variant results in a deleterious effect to the protein that is sufficient to be disease-causing (PMID: 26032686). This variant has been reported in multiple individuals with Wilson disease (PMID: 30655162, 17949296, 27982462, 33668890, 11405812, 12756138, 11775208, 14986826, 16649058, 26483271, 27022412). This variant is present in 49 of 280706 total alleles in the Genome Aggregation Database (http://gnomad.broadinstitute.org/). This variant was detected in multiple affected individuals as compound heterozygous (in trans) with a likely pathogenic or pathogenic variant, which is consistent with autosomal recessive inheritance (PMID: 25825851, 24476933, 28123513,27398169, 11405812, 11775208, 14986826, 16649058, 26483271) and was reported to be homozygous in one affected individual (PMID: 33668890). This variant has been reported to co-segregate with Wilson disease in more than 13 affected individuals in more than one family (PMID: 33668890, 18034201). -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jan 24, 2024	This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 935 of the ATP7B protein (p.Thr935Met). This variant is present in population databases (rs750019452, gnomAD 0.2%). This missense change has been observed in individual(s) with Wilson disease (PMID: 11775208, 14986826, 16649058, 26483271, 27022412). ClinVar contains an entry for this variant (Variation ID: 188713). 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: 26032686). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 13, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 11, 2020	The ATP7B c.2804C>T; p.Thr935Met variant (rs750019452) is reported in the literature in multiple individuals with Wilson disease who are compound heterozygous with another ATP7B variant (Chen 2014, Chen 2019, Gu 2003, Lepori 2007, Mak 2008, Van Biervliet 2015, Wu 2000). This variant is reported in ClinVar (Variation ID: 188713), and observed in the East Asian population with an allele frequency of 0.24% (46/19536 alleles) in the Genome Aggregation Database. The threonine at codon 935 is highly conserved, and computational algorithms (SIFT, PolyPhen2) predict this variant to be damaging to the protein. Based on the above information, this variant is considered likely pathogenic. References: Chen L et al. A novel ATP7B gene mutation in a liver failure patient with normal ceruloplasmin and low serum alkaline phosphatase. Gene. 2014 Mar 15;538(1):204-6. Chen YC et al. Contribution of intragenic deletions to mutation spectrum in Chinese patients with Wilson's disease and possible mechanism underlying ATP7B gross deletions. Parkinsonism Relat Disord. 2019 May;62:128-133. Gu YH et al. Mutation spectrum and polymorphisms in ATP7B identified on direct sequencing of all exons in Chinese Han and Hui ethnic patients with Wilson's disease. Clin Genet. 2003 Dec;64(6):479-84. Lepori MB et al. Twenty-four novel mutations in Wilson disease patients of predominantly Italian origin. Genet Test. 2007 Fall;11(3):328-32. Mak CM et al. Mutational analysis of 65 Wilson disease patients in Hong Kong Chinese: identification of 17 novel mutations and its genetic heterogeneity. J Hum Genet. 2008;53(1):55-63. Van Biervliet S et al. Clinical zinc deficiency as early presentation of Wilson disease. J Pediatr Gastroenterol Nutr. 2015 Apr;60(4):457-9. Wu Z et al. Identification and analysis of mutations of the Wilson disease gene in Chinese population. Chin Med J (Engl). 2000 Jan;113(1):40-3. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Apr 04, 2023	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 24094725, 17949296, 34598035, 35041927, 35357466, 26032686, 23607698, 24476933, 22692182, 11775208, 17680703, 18034201, 18760268, 26483271, 25825851, 14986826, 11405812, 21219664, 11715435, 9829905, 10447265, 30609409, 30655162, 21796144, 30275481, 24475083, 31980526, 32043565, 27982432, 16649058, 30884209, 31589614, 33668890, 27022412, 33763395, 32794656, 35314707, 35470480, 35385937) -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 22, 2023	PP3, PP4, PM2, PS3, PS4_moderate -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Pathogenic	0.45
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D;D;.;.;.;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.84	T;T;T;D;D;D
M_CAP	Pathogenic	0.43	D
MetaRNN	Pathogenic	0.78	D;D;D;D;D;D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Pathogenic	3.0	M;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-5.6	D;D;D;D;.;D
REVEL	Pathogenic	0.84
Sift	Pathogenic	0.0	D;D;D;D;.;D
Sift4G	Pathogenic	0.0010	D;D;D;D;D;D
Polyphen		1.0	D;D;P;D;D;D
Vest4		0.86
MutPred		0.87		Loss of catalytic residue at T935 (P = 0.0077);.;.;.;.;Loss of catalytic residue at T935 (P = 0.0077);
MVP		0.99
MPC		0.38
ClinPred		0.35	T
GERP RS		6.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.90
gMVP		0.93

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: rs750019452; hg19: chr13-52523859; COSMIC: COSV54439574; COSMIC: COSV54439574;