rs7540883
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Variant summary
Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1
The NM_213653.4(HJV):āc.929C>Gā(p.Ala310Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00392 in 1,614,126 control chromosomes in the GnomAD database, including 194 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (ā ā ).
Frequency
Genomes: š 0.021 ( 105 hom., cov: 32)
Exomes š: 0.0021 ( 89 hom. )
Consequence
HJV
NM_213653.4 missense
NM_213653.4 missense
Scores
2
5
Clinical Significance
Conservation
PhyloP100: 2.51
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 Benign. Variant got -18 ACMG points.
PM1
?
In a disulfide_bond (size 150) in uniprot entity RGMC_HUMAN there are 12 pathogenic changes around while only 2 benign (86%) in NM_213653.4
BP4
?
Computational evidence support a benign effect (MetaRNN=0.012807339).
BP6
?
Variant 1-146018429-G-C is Benign according to our data. Variant chr1-146018429-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 292430.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BA1
?
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0715 is higher than 0.05.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HJV | NM_213653.4 | c.929C>G | p.Ala310Gly | missense_variant | 4/4 | ENST00000336751.11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HJV | ENST00000336751.11 | c.929C>G | p.Ala310Gly | missense_variant | 4/4 | 2 | NM_213653.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0212 AC: 3219AN: 152184Hom.: 105 Cov.: 32
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GnomAD3 exomes AF: 0.00565 AC: 1421AN: 251410Hom.: 45 AF XY: 0.00404 AC XY: 549AN XY: 135882
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GnomAD4 exome AF: 0.00212 AC: 3103AN: 1461824Hom.: 89 Cov.: 32 AF XY: 0.00187 AC XY: 1363AN XY: 727212
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GnomAD4 genome ? AF: 0.0211 AC: 3219AN: 152302Hom.: 105 Cov.: 32 AF XY: 0.0206 AC XY: 1536AN XY: 74488
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hemochromatosis type 2A Benign:2
Benign, no assertion criteria provided | clinical testing | Natera, Inc. | Dec 04, 2019 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
not specified Benign:1
Benign, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Jul 31, 2024 | - - |
not provided Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 31, 2024 | - - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
MetaRNN
Benign
T;T;T;T;T
PROVEAN
Benign
N;N;N;N;.
Sift
Benign
T;T;T;T;.
Sift4G
Benign
T;T;T;T;.
Vest4
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at