rs74315324
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Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_213653.4(HJV):c.976C>T(p.Arg326Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.0000409 in 1,613,990 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000044 ( 0 hom. )
Consequence
HJV
NM_213653.4 stop_gained
NM_213653.4 stop_gained
Scores
1
1
Clinical Significance
Conservation
PhyloP100: 4.00
Genes affected
HJV (HGNC:4887): (hemojuvelin BMP co-receptor) The product of this gene is involved in iron metabolism. It may be a component of the signaling pathway which activates hepcidin or it may act as a modulator of hepcidin expression. It could also represent the cellular receptor for hepcidin. Two uORFs in the 5' UTR negatively regulate the expression and activity of the encoded protein. Alternatively spliced transcript variants encoding different isoforms have been identified for this gene. Defects in this gene are the cause of hemochromatosis type 2A, also called juvenile hemochromatosis (JH). JH is an early-onset autosomal recessive disorder due to severe iron overload resulting in hypogonadotrophic hypogonadism, hepatic fibrosis or cirrhosis and cardiomyopathy, occurring typically before age of 30. [provided by RefSeq, Oct 2015]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 5 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 1-146018382-G-A is Pathogenic according to our data. Variant chr1-146018382-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 2366.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HJV | NM_213653.4 | c.976C>T | p.Arg326Ter | stop_gained | 4/4 | ENST00000336751.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HJV | ENST00000336751.11 | c.976C>T | p.Arg326Ter | stop_gained | 4/4 | 2 | NM_213653.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152180Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251340Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135862
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GnomAD4 exome AF: 0.0000445 AC: 65AN: 1461810Hom.: 0 Cov.: 32 AF XY: 0.0000358 AC XY: 26AN XY: 727214
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152180Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74342
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hemochromatosis type 2A Pathogenic:4
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 12, 2024 | Variant summary: HJV c.976C>T (p.Arg326X) results in a premature termination codon located in the last exon, therefore not expected to cause nonsense mediated decay (NMD), but is predicted to cause a truncation of the encoded protein, removing a large part of the 426 amino acid long protein (InterPro). Truncations downstream of this position have been reported in affected individuals (HGMD). The variant allele was found at a frequency of 1.2e-05 in 251340 control chromosomes (gnomAD). c.976C>T has been reported in the literature in compound heterozygous individuals affected with Hemochromatosis Type 2A (Papanikolaou_2003, Wallace_2004). These data indicate that the variant is likely associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jul 22, 2024 | - - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2004 | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Aug 25, 2021 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 18, 2023 | This sequence change creates a premature translational stop signal (p.Arg326*) in the HJV gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 101 amino acid(s) of the HJV protein. This variant is present in population databases (rs74315324, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with juvenile hemochromatosis (PMID: 14647275). ClinVar contains an entry for this variant (Variation ID: 2366). This variant disrupts a region of the HJV protein in which other variant(s) (p.Gly336*) have been determined to be pathogenic (PMID: 30195625; Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
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Name
Calibrated prediction
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Prediction
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Uncertain
Vest4
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at