rs752850609

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong

The NM_000053.4(ATP7B):​c.1847G>A​(p.Arg616Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,614,058 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 Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

ATP7B
NM_000053.4 missense

Scores

9
7
3

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:16

Conservation

PhyloP100: 7.50
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 14 ACMG points.

PM1
In a domain HMA 6 (size 66) in uniprot entity ATP7B_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_000053.4
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.858
PP5
Variant 13-51964894-C-T is Pathogenic according to our data. Variant chr13-51964894-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 552606.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr13-51964894-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
ATP7BNM_000053.4 linkuse as main transcriptc.1847G>A p.Arg616Gln missense_variant 5/21 ENST00000242839.10 NP_000044.2 P35670-1B7ZLR4A0A024RDX3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ATP7BENST00000242839.10 linkuse as main transcriptc.1847G>A p.Arg616Gln missense_variant 5/211 NM_000053.4 ENSP00000242839.5 P35670-1

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152066
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000192
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000481
AC:
12
AN:
249570
Hom.:
0
AF XY:
0.0000443
AC XY:
6
AN XY:
135404
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000579
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000883
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000157
AC:
23
AN:
1461874
Hom.:
0
Cov.:
31
AF XY:
0.0000151
AC XY:
11
AN XY:
727242
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000447
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000171
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152184
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74402
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000193
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000574
Hom.:
0
Bravo
AF:
0.0000340
ExAC
AF:
0.0000497
AC:
6

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:16
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Wilson disease Pathogenic:12
Pathogenic, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpApr 30, 2018Variant summary: ATP7B c.1847G>A (p.Arg616Gln) results in a conservative amino acid change located in the Heavy metal-associated domain of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.9e-05 in 246238 control chromosomes. This frequency is not higher than expected for a pathogenic variant in ATP7B causing Wilson Disease (4.9e-05 vs 0.0054), allowing no conclusion about variant significance. c.1847G>A has been reported in the literature in multiple individuals affected with Wilson Disease as both a compound heterozygous and homozygous allele (Loudianos_2003, Ljubic_2016). These data indicate that the variant is very likely to be associated with disease. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 25, 2024This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 616 of the ATP7B protein (p.Arg616Gln). This variant is present in population databases (rs752850609, gnomAD 0.009%). This missense change has been observed in individual(s) with Wilson disease (PMID: 12885331, 21610751, 22735241, 26799313). ClinVar contains an entry for this variant (Variation ID: 552606). 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%. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingCounsylJun 23, 2017- -
Pathogenic, criteria provided, single submitterclinical testingBaylor GeneticsMar 26, 2024- -
Pathogenic, criteria provided, single submitterclinical testingAll of Us Research Program, National Institutes of HealthAug 06, 2024This missense variant replaces arginine with glutamine at codon 616 of the ATP7B protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with Wilson disease (PMID: 10502777, 12885331, 16283883, 17264425, 18286826, 18034201, 21610751, 22735241, 23518715, 23789284, 26799313). In many of these affected individuals, this variant has been determined to be homozygous or compound heterozygous with another pathogenic variant in the same gene (PMID: 12885331, 17264425, 21610751, 22735241, 23518715, 26799313). These data indicate that this variant contributes to Wilson disease in an autosomal recessive manner. This variant has been identified in 12/249570 chromosomes in the general population by the Genome Aggregation Database (gnomAD). A different variant occurring at the same codon, p.Arg616Trp, is classified as pathogenic (Clinvar Variation ID: 863093), indicating that arginine at this position is important for ATP7b protein function. Based on the available evidence, this variant is classified as Pathogenic. -
Pathogenic, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsAug 02, 2021- -
Pathogenic, criteria provided, single submitterclinical testingJuno Genomics, Hangzhou Juno Genomics, Inc-PM5_Supporting+PM2_Supporting+PS3_Supporting+PM3_VeryStrong+PP4 -
Pathogenic, criteria provided, single submitterclinical testingCentre for Mendelian Genomics, University Medical Centre LjubljanaApr 09, 2019This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PM3,PM5,PP2,PP3. -
Pathogenic, no assertion criteria providedclinical testingNatera, Inc.Jul 14, 2020- -
Pathogenic, criteria provided, single submitterclinical testingGenome-Nilou LabAug 10, 2021- -
Pathogenic, criteria provided, single submittercurationLaboratory of Medical Genetics, National & Kapodistrian University of AthensFeb 01, 2024- -
Pathogenic, no assertion criteria providedresearchGenomics And Bioinformatics Analysis Resource, Columbia University-- -
not provided Pathogenic:4
Likely pathogenic, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
Pathogenic, criteria provided, single submitterclinical testingGeneDxJun 08, 2024Not observed at significant frequency in large population cohorts (gnomAD); 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: 16283883, 18286826, 17264425, 32118851, 23789284, 23518715, 12885331, 22735241, 18371106, 18034201, 10502777, 20517649, 21610751, 17919502, 30702195, 26799313, 35271763) -
Pathogenic, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenApr 01, 2024ATP7B: PM3:Very Strong, PM2, PM5, PP4, PS3:Supporting -
Likely pathogenic, no assertion criteria providedclinical testingGenome Diagnostics Laboratory, University Medical Center Utrecht-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.58
BayesDel_addAF
Pathogenic
0.27
D
BayesDel_noAF
Pathogenic
0.35
CADD
Pathogenic
27
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.83
D;D;.;.;.;.
Eigen
Pathogenic
0.78
Eigen_PC
Pathogenic
0.80
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Uncertain
0.97
D;D;D;D;D;D
M_CAP
Uncertain
0.24
D
MetaRNN
Pathogenic
0.86
D;D;D;D;D;D
MetaSVM
Uncertain
0.56
D
MutationAssessor
Benign
1.5
L;.;L;.;.;.
PrimateAI
Benign
0.38
T
PROVEAN
Uncertain
-3.7
D;D;D;D;.;D
REVEL
Uncertain
0.63
Sift
Uncertain
0.0010
D;T;D;D;.;D
Sift4G
Uncertain
0.0020
D;D;D;D;D;D
Polyphen
1.0
D;D;D;D;D;D
Vest4
0.86
MVP
0.98
MPC
0.40
ClinPred
0.95
D
GERP RS
6.0
Varity_R
0.77
gMVP
0.68

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: rs752850609; hg19: chr13-52539030; COSMIC: COSV54438671; COSMIC: COSV54438671; API