rs749553271
Variant summary
Our verdict is Pathogenic. Variant got 22 ACMG points: 22P and 0B. PVS1PM2PP3_StrongPP5_Very_Strong
The NM_000410.4(HFE):c.892G>T(p.Glu298Ter) variant causes a stop gained, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. E298E) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_000410.4 stop_gained, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 22 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HFE | NM_000410.4 | c.892G>T | p.Glu298Ter | stop_gained, splice_region_variant | 4/6 | ENST00000357618.10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HFE | ENST00000357618.10 | c.892G>T | p.Glu298Ter | stop_gained, splice_region_variant | 4/6 | 1 | NM_000410.4 | P3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152160Hom.: 0 Cov.: 31
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461716Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1AN XY: 727166
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152160Hom.: 0 Cov.: 31 AF XY: 0.0000404 AC XY: 3AN XY: 74328
ClinVar
Submissions by phenotype
Hereditary hemochromatosis Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 21, 2016 | While this particular variant has not been reported in the literature, truncating variants in HFE are known to contribute to hemochromatosis when homozygous or present with a second pathogenic allele in HFE (PMID: 9482913, 10557317, 10381492, 24920245, 10930379). This sequence change creates a premature translational stop signal at codon 298 (p.Glu298*) of the HFE gene. It is expected to result in an absent or disrupted protein product. For these reasons, this variant has been classified as Pathogenic. - |
Hemochromatosis type 1 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 25, 2023 | Variant summary: HFE c.892G>T (p.Glu298X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay. Other truncations have been cited in association with Hemochromatosis in HGMD. The variant was absent in 251016 control chromosomes (gnomAD). To our knowledge, no occurrence of c.892G>T in individuals affected with Hemochromatosis Type 1 and no experimental evidence demonstrating its impact on protein function have been reported. One clinical diagnostic laboratory has submitted clinical-significance assessments for this variant to ClinVar after 2014, classifying the variant as pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at