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LYFE SCIENCES
Project: HERA
NM_000143.4:c.1366G>T
p.Val456Leu  ·  FH
ACMG/AMP
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Classification rationale
1

The FH c.1366G>T (p.Val456Leu) variant has been reported in ClinVar as a variant of uncertain significance by one clinical laboratory.

clinvar ↗
2

This variant is rare in population databases, with gnomAD v2.1 AF 0.00318% (1/31,398 alleles) and gnomAD v4.1 AF 0.00019% (3/1,614,014 alleles), which are both below the 0.1% PM2 threshold and well below the BS1 and BA1 frequency thresholds.

gnomad_v2 ↗ gnomad_v4 ↗
3

Computational evidence supports a deleterious missense effect, with REVEL 0.913 and BayesDel 0.286106, while SpliceAI predicts no significant splice impact for this variant (max delta score 0.00).

spliceai ↗
Applied criteria
Met
Not met
Not assessed
N/A
Very strong
Strong
Moderate
Supporting
Pathogenic evidence
PVS
PVS1
PS
PS1
PS2
PS3
PS4
PM
PM1
PM2
PM3
PM4
PM5
PM6
PP
PP1
PP2
PP3
PP4
PP5
Benign evidence
BA
BA1
BS
BS1
BS2
BS3
BS4
BP
BP1
BP2
BP3
BP4
BP5
BP6
BP7
PVS1
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Rationale
Select a criterion to inspect its explanation.
Evidence used
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Gaps remaining
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Rule
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Publications
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Research and evidence
gnomAD v2.1 evidence
v2.1
gnomAD v4.1 evidence
v4.1
01
Population
gnomAD v2.1This variant is present in gnomAD v2.1 (AF= 3.18492e-05; MAF= 0.00318%, 1/31398 alleles, homozygotes = 0) and has highest observed frequency in the European (Finnish) population (AF= 0.000287687; MAF= 0.02877%, 1/3476 alleles, homozygotes = 0).
gnomAD v4.1This variant is present in gnomAD v4.1 (AF= 1.85872e-06; MAF= 0.00019%, 3/1614014 alleles, homozygotes = 0) and has highest observed frequency in the European (Finnish) population (AF= 4.68589e-05; MAF= 0.00469%, 3/64022 alleles, homozygotes = 0).
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory). (ClinVarID = 4257325)
ClinVar ↗
Functional evidence
03
Functional
OncoKB: Unknown Oncogenic Effect
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. FH, an enzyme that converts fumarate to malate in the TCA cycle, is infrequently altered in cancer.
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.913. BayesDel score = 0.286106.
SpliceAI ↗
COSMIC evidence
05
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant does not lie in a statistically significant hotspot.
ResidueV456
Hotspots ↗