LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Variant classification summary
NM_000410.4:c.193A>T
HFE
· NP_000401.1:p.(Ser65Cys)
· NM_000410.4
GRCh37: chr6:26091185 A>T
·
GRCh38: chr6:26090957 A>T
Gene:
HFE
Transcript:
NM_000410.4
Final call
VUS
Variant details
Gene
HFE
Transcript
NM_000410.4
Protein
NP_000401.1:p.(Ser65Cys)
gnomAD AF
0.013639900674560494 (v4.1)
ClinVar
Uncertain significance
OncoKB
Unknown Oncogenic Effect
Classification rationale
Interpretation summary
Generated evidence synthesis
1
PS4 is not met because the exact-variant case-control data yield OR 1.50 with 95% CI 0.62–3.64, failing the required OR >5.0 and CI-not-including-1.0 thresholds.
2
PP4 and BP5 remain not assessed because case-level phenotype/family-history and alternate-molecular-basis information are unavailable.
3
PP5 and BP6 are not met because ClinVar has zero exact-variant expert-panel submissions and ordinary laboratory or literature-only assertions are excluded.
4
The variant is missense, so PP3 and BP4 are adjudicated exclusively through the REVEL path under the generic rules.
5
REVEL 0.549 is below the PP3 supporting cutoff and above the BP4 supporting cutoff; neither computational criterion is met.
Final determination:
Under the generic ACMG/AMP 2015 fallback, no pathogenic, likely pathogenic, benign, or likely benign combination is satisfied, so the variant is classified as VUS.
Criteria assessment
ACMG/AMP criteria review
Criteria shown when status is available
All criteria require review: For research and educational purposes only.
| Criterion | Status | Rationale | Evidence used |
|---|---|---|---|
| PVS1 | N/A | Not applicable: PVS1 requires a null variant (nonsense, frameshift, canonical splice, start-loss or stop-loss), and this is a missense variant. |
pvs1_generic_framework
generic_acmg_combination_rules
|
| PS1 | Not met | Not met: no different-nucleotide HFE variant producing p.Ser65Cys is established as pathogenic in the reviewed evidence. |
clinvar
PMID:16132052
PMID:12377814
|
| PS2 | Not assessed | Not assessed: no documented de novo occurrence with confirmed maternity and paternity, disease phenotype, and no family history is available. |
|
| PS3 | Not assessed | Not assessed: reviewed studies provide clinical observations but no validated in vitro or in vivo assay demonstrating a damaging effect of HFE p.Ser65Cys. |
PMID:16132052
PMID:12377814
PMID:11943417
|
| PS4 | Not met | Not met: HFE S65C had OR 1.50 (95% CI 0.62–3.64), below the >5.0 threshold and with a confidence interval including 1.0. |
PMID:12377814
|
| PM1 | Not met | Not met: gnomAD v4.1 reports AF 0.0136399, and no validated HFE hotspot or benign-variation-free critical domain is established. |
gnomad_v4
gnomad_v2
hotspots
PMID:16132052
PMID:12377814
|
| PM2 | Not met | Not met: gnomAD v4.1 AF is 1.36%, far above the 0.01% PM2 threshold, with 195 homozygotes observed. |
gnomad_v2
gnomad_v4
|
| PM3 | Not assessed | Not assessed: 12 C282Y/S65C compound heterozygotes were reported, but parental or offspring testing to establish trans phase was not documented. |
PMID:11943417
PMID:16132052
|
| PM4 | N/A | Not applicable: PM4 requires a protein-length change, and this is a missense variant. |
pvs1_generic_framework
generic_acmg_combination_rules
|
| PM5 | Not met | Not met: no different missense substitution at HFE residue 65 is established as pathogenic in the reviewed comparator evidence. |
pm5_candidates
PMID:16132052
PMID:12377814
|
| PM6 | Not assessed | Not assessed: no affected proband with assumed de novo HFE c.193A>T and incomplete parental confirmation is documented. |
|
| PP1 | Not assessed | Not assessed: family data include six S65C-carrying relatives and 12 C282Y/S65C individuals but do not demonstrate co-segregation in multiple affected family members. |
PMID:12377814
PMID:11943417
|
| PP2 | Not met | Not met: HFE p.Ser65Cys has gnomAD v4.1 AF 0.0136399, inconsistent with a low rate of benign missense variation. |
gnomad_v4
gnomad_v2
PMID:16132052
PMID:12377814
|
| PP3 | Not met | Not met: missense-path REVEL score 0.549 is below the PP3 supporting threshold of 0.644. |
revel
|
| PP4 | Not assessed | Not assessed: the case phenotype and family history are unavailable, so specificity for a single genetic etiology cannot be judged. |
PMID:12377814
PMID:11943417
PMID:16132052
|
| PP5 | Not met | Not met: ClinVar reports zero exact-variant expert-panel submissions, so no qualifying Pathogenic or Likely pathogenic source supports PP5. |
clinvar
|
| BA1 | Not met | Not met: gnomAD v4.1 grpmax FAF is 1.61%, below the 5% BA1 threshold, and the 2.64% Amish popmax is based on only 910 alleles. |
gnomad_v2
gnomad_v4
PMID:16132052
|
| BS1 | Not assessed | Not assessed: grpmax FAF is 1.61% above the 1% default, but HFE S65C has reduced, variable penetrance and no maximum-credible-frequency inputs are available. |
gnomad_v2
gnomad_v4
PMID:16132052
|
| BS2 | Not met | Not met: 195 gnomAD v4.1 homozygotes are observed, but HFE disease is late-onset/reduced-penetrance and healthy adult status with early full penetrance is not established. |
gnomad_v2
gnomad_v4
PMID:12377814
PMID:16132052
|
| BS3 | Not assessed | Not assessed: reviewed studies provide clinical observations but no well-established assay showing that HFE p.Ser65Cys has no damaging effect on protein function or splicing. |
PMID:16132052
PMID:12377814
PMID:11943417
|
| BS4 | Not assessed | Not assessed: no affected-family-member dataset shows absence of HFE c.193A>T, and phenocopies or additional pathogenic variants cannot be evaluated. |
|
| BP1 | Not met | Not met: HFE hereditary hemochromatosis is chiefly associated with recurrent missense alleles C282Y and H63D, not primarily truncating variants. |
PMID:16132052
PMID:10194428
|
| BP2 | Not assessed | Not assessed: reported C282Y/S65C observations are compound heterozygotes, with no cis observation and no fully penetrant dominant HFE disorder established. |
PMID:11943417
PMID:16132052
|
| BP3 | N/A | Not applicable: BP3 requires an in-frame indel in a repeat region, and this is a missense variant. |
pvs1_generic_framework
generic_acmg_combination_rules
|
| BP4 | Not met | Not met: missense-path REVEL score 0.549 exceeds the BP4 supporting threshold of 0.29. |
revel
|
| BP5 | Not assessed | Not assessed: no case-level evidence shows an alternate molecular basis for the patient's disease. |
PMID:12377814
PMID:11943417
|
| BP6 | Not met | Not met: ClinVar reports zero exact-variant expert-panel submissions, so single-laboratory Benign labels cannot support BP6. |
clinvar
|
| BP7 | N/A | Not applicable: BP7 requires a synonymous variant, and this is a missense variant. |
generic_acmg_combination_rules
|
Disclaimer:
The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.