1-146019594-A-G
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP3_StrongPP5_Moderate
The NM_213653.4(HJV):c.238T>C(p.Cys80Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000359 in 1,613,538 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C80G) has been classified as Likely pathogenic.
Frequency
Consequence
NM_213653.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
HJV | NM_213653.4 | c.238T>C | p.Cys80Arg | missense_variant | Exon 3 of 4 | ENST00000336751.11 | NP_998818.1 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152182Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00000816 AC: 2AN: 244982Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 133208
GnomAD4 exome AF: 0.0000383 AC: 56AN: 1461356Hom.: 0 Cov.: 35 AF XY: 0.0000426 AC XY: 31AN XY: 726932
GnomAD4 genome AF: 0.0000131 AC: 2AN: 152182Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74350
ClinVar
Submissions by phenotype
Hemochromatosis type 2A Pathogenic:1
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not provided Pathogenic:1
This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 80 of the HJV protein (p.Cys80Arg). This variant is present in population databases (rs28940586, gnomAD 0.004%). This missense change has been observed in individual(s) with clinical features of juvenile hemochromatosis (PMID: 14982867, 15710580). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 2369). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Experimental studies have shown that this missense change affects HJV function (PMID: 18827264). This variant disrupts the p.Cys80 amino acid residue in HJV. Other variant(s) that disrupt this residue have been determined to be pathogenic (internal data). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at