13-51942497-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The ENST00000242839.10(ATP7B):​c.3301G>A​(p.Gly1101Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. G1101G) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

ATP7B
ENST00000242839.10 missense

Scores

15
3
1

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9

Conservation

PhyloP100: 7.86
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM1
In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in ENST00000242839.10
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.992
PP5
Variant 13-51942497-C-T is Pathogenic according to our data. Variant chr13-51942497-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 188808.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51942497-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ATP7BNM_000053.4 linkuse as main transcriptc.3301G>A p.Gly1101Arg missense_variant 15/21 ENST00000242839.10 NP_000044.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ATP7BENST00000242839.10 linkuse as main transcriptc.3301G>A p.Gly1101Arg missense_variant 15/211 NM_000053.4 ENSP00000242839 P1P35670-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000401
AC:
1
AN:
249576
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135404
show subpopulations
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:
0.0000327
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:
1461888
Hom.:
0
Cov.:
32
AF XY:
0.00000550
AC XY:
4
AN XY:
727244
show subpopulations
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:
0.0000464
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:9
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Wilson disease Pathogenic:9
Pathogenic, criteria provided, single submitterclinical testingNeuberg Centre For Genomic Medicine, NCGMMay 20, 2023The observed missense c.3301G>A(p.Gly1101Arg) variant in ATP7B gene has been reported previously in homozygous state in multiple individuals affected with Wilson disease (Singh N, et al., 2019; Aggarwal A, et al., 2013). Experimental studies have shown that this missense change affects ATP7B function (Luoma LM, et al., 2010). The p.Gly1101Arg variant has been reported with allele frequency of 0.0004% in gnomAD Exomes. This variant has been submitted to the ClinVar database as Likely Pathogenic / Pathogenic. The amino acid change p.Gly1101Arg in ATP7B is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Gly at position 1101 is changed to a Arg changing protein sequence and it might alter its composition and physico-chemical properties. Multiple lines of computational evidences (Polyphen - Probably damaging , SIFT - Damaging and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitterliterature onlyCounsylMay 30, 2014- -
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsFeb 29, 2024- -
Likely pathogenic, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesApr 06, 2019The ATP7B c.3301G>A; p.Gly1101Arg variant (rs786204483) is reported in two individuals with Wilson disease who are homozygous for the variant (reported as G1102R in Thomas 1995). Functional assays show the variant protein is unable to complement ccc2 function under low iron conditions, supportive of it being deleterious. (Luoma 2010). This variant is reported in ClinVar (Variation ID: 188808). It is only observed on one allele in the Genome Aggregation Database, indicating it is not a common polymorphism. The glycine at codon 1101 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, this variant is considered to be likely pathogenic. REFERENCES Luoma LM et al. Functional analysis of mutations in the ATP loop of the Wilson disease copper transporter, ATP7B. Hum Mutat. 2010 May;31(5):569-77. Thomas GR et al. The Wilson disease gene: spectrum of mutations and their consequences. Nat Genet. 1995 Feb;9(2):210-7. -
Pathogenic, criteria provided, single submitterclinical testingRevvity Omics, RevvitySep 23, 2023- -
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpMay 19, 2023For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects ATP7B function (PMID: 20333758). 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. ClinVar contains an entry for this variant (Variation ID: 188808). This missense change has been observed in individual(s) with Wilson disease (PMID: 7626145, 23551039, 31059521). This variant is present in population databases (rs786204483, gnomAD 0.003%). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1101 of the ATP7B protein (p.Gly1101Arg). -
Pathogenic, criteria provided, single submitterclinical testingCentogene AG - the Rare Disease Company-- -
Likely pathogenic, criteria provided, single submitterclinical testingGenome-Nilou LabAug 10, 2021- -
Pathogenic, criteria provided, single submitterclinical testingArcensusFeb 01, 2013- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.98
BayesDel_addAF
Pathogenic
0.51
D
BayesDel_noAF
Pathogenic
0.60
CADD
Pathogenic
27
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.98
D;D;.;.;.;.;.
Eigen
Pathogenic
0.88
Eigen_PC
Pathogenic
0.80
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Pathogenic
1.0
D;D;D;D;D;D;D
M_CAP
Pathogenic
0.86
D
MetaRNN
Pathogenic
0.99
D;D;D;D;D;D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
3.7
H;.;.;.;.;.;.
MutationTaster
Benign
1.0
D;D;D;D;D;D;D
PrimateAI
Uncertain
0.72
T
PROVEAN
Pathogenic
-7.0
D;D;D;D;D;.;D
REVEL
Pathogenic
0.98
Sift
Uncertain
0.0010
D;D;D;D;D;.;D
Sift4G
Uncertain
0.0020
D;D;D;D;D;D;D
Polyphen
1.0
D;D;D;B;D;D;D
Vest4
0.92
MutPred
0.96
Loss of sheet (P = 0.0181);.;.;.;.;.;.;
MVP
0.99
MPC
0.41
ClinPred
1.0
D
GERP RS
4.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.94
gMVP
0.96

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.

Other links and lift over

dbSNP: rs786204483; hg19: chr13-52516633; API