rs750019452

Positions:

chr13-51949723-G-A

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM1PM2PP3PP5_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 Benign.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000044 ( 1 hom. )

Consequence

ATP7B
NM_000053.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:15

Conservation

PhyloP100: 9.94

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]

ATP7B links:

ATP7B (HGNC:):

ATP7B links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 13 ACMG points.

PM1

In a transmembrane_region Helical (size 22) in uniprot entity ATP7B_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) 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	Protein	UniProt
ATP7B	NM_000053.4 linkuse as main transcript	c.2804C>T	p.Thr935Met	missense_variant	12/21	ENST00000242839.10	NP_000044.2	P35670-1B7ZLR4A0A024RDX3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ATP7B	ENST00000242839.10 linkuse as main transcript	c.2804C>T	p.Thr935Met	missense_variant	12/21	1	NM_000053.4	ENSP00000242839.5		P35670-1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152108

Hom.:

Cov.:

show subpopulations

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:

AN:

249318

Hom.:

AF XY:

0.000185

AC XY:

AN XY:

135290

show subpopulations

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:

AN:

1461776

Hom.:

Cov.:

AF XY:

0.0000440

AC XY:

AN XY:

727188

show subpopulations

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:

AN:

152108

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74282

show subpopulations

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.:

Bravo

AF:

0.000102

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ExAC

AF:

0.000174

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:15

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Wilson disease

Pathogenic:11

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	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. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 27, 2024	- -
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. -
Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	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, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Sep 23, 2024	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	Fulgent Genetics, Fulgent Genetics	May 14, 2024	- -
Likely pathogenic, criteria provided, single submitter	literature only	Counsyl	Mar 03, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Nov 23, 2020	- -

not provided

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 07, 2024	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, 37020998, 38167091, ZhangT2023[preprint], 36456202, 37031186, 36459106, 37701133) -
Pathogenic, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 22, 2023	PP3, PP4, PM2, PS3, PS4_moderate -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	ATP7B: PM3:Very Strong, PM2 -

ATP7B-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 04, 2024

The ATP7B c.2804C>T variant is predicted to result in the amino acid substitution p.Thr935Met. This variant has been documented in the homozygous or compound heterozygous state in individuals with Wilson disease (Wu et al. 2000. PubMed ID: 11775208), and functional analysis suggests that this change results in compromised copper excretion in vitro (Zhu et al. 2015. PubMed ID: 26032686). In ClinVar, this variant is interpreted as pathogenic and likely pathogenic (https://www.ncbi.nlm.nih.gov/clinvar/variation/188713/). This variant is reported in 0.24% of alleles in individuals of East Asian descent in gnomAD. This variant is interpreted as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.61

BayesDel_addAF

Uncertain

0.16

BayesDel_noAF

Pathogenic

0.45

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.94

D;D;.;.;.;.

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.84

T;T;T;D;D;D

M_CAP

Pathogenic

0.43

MetaRNN

Pathogenic

0.78

D;D;D;D;D;D

MetaSVM

Pathogenic

0.96

MutationAssessor

Pathogenic

3.0

M;.;.;.;.;.

PrimateAI

Uncertain

0.62

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over