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
Consequence
NM_000053.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ATP7B | NM_000053.4 | c.1847G>A | p.Arg616Gln | missense_variant | Exon 5 of 21 | ENST00000242839.10 | NP_000044.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000197 AC: 3AN: 152066Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000481 AC: 12AN: 249570Hom.: 0 AF XY: 0.0000443 AC XY: 6AN XY: 135404
GnomAD4 exome AF: 0.0000157 AC: 23AN: 1461874Hom.: 0 Cov.: 31 AF XY: 0.0000151 AC XY: 11AN XY: 727242
GnomAD4 genome AF: 0.0000197 AC: 3AN: 152184Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2AN XY: 74402
ClinVar
Submissions by phenotype
Wilson disease Pathogenic:12
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Variant 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. -
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This 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. -
PM5_Supporting+PM2_Supporting+PS3_Supporting+PM3_VeryStrong+PP4 -
This 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. -
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This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PM3,PM5,PP2,PP3. -
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not provided Pathogenic:4
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Not 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) -
ATP7B: PM3:Very Strong, PM2, PM5, PP4, PS3:Supporting -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at