Back
LYFE SCIENCES
Project: HERA
NM_001369786.1:c.40G>A
p.Val14Ile  ·  KRAS
Starting
Initialising…
0%
Legacy Engine
Ready
View Legacy →
Classification rationale
1

The KRAS c.40G>A (p.Val14Ile) variant has been reported in ClinVar as pathogenic, including expert panel review, and it was reported as a de novo germline KRAS mutation in Noonan syndrome.

clinvar ↗ PMID:16474405 ↗
2

This variant is absent from gnomAD v2.1 and is present at very low frequency in gnomAD v4.1 at 2/1612846 alleles (0.00012%), which is below the KRAS RASopathy VCEP benign frequency thresholds.

gnomad_v2 ↗ gnomad_v4 ↗ cspec ↗
3

In the RASopathy VCEP approved functional studies, p.Val14Ile is listed as a pathogenic control in approved RAS activation, MEK activation, and ERK activation assay classes citing PMID:20949621, supporting abnormal KRAS signaling consistent with a gain-of-function effect.

PMID:20949621 ↗
4

Computational data support a damaging missense effect, with REVEL 0.803 above the PP3 threshold of 0.7, BayesDel 0.289645, and SpliceAI showing no significant splice impact (max delta score 0.01).

cspec ↗ 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
—
—
Rationale
Select a criterion to inspect its explanation.
Evidence used
  • —
Gaps remaining
  • —
Rule
—
Publications
—
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= 0; MAF= 0.00000%, 0/249502 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/16070 alleles, homozygotes = 0).
gnomAD v4.1This variant is present in gnomAD v4.1 (AF= 1.24004e-06; MAF= 0.00012%, 2/1612846 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.69593e-06; MAF= 0.00017%, 2/1179292 alleles, homozygotes = 0); grpmax FAF= 2.8e-07.
gnomAD v2 ↗ gnomAD v4 ↗
ClinVar evidence
02
ClinVar
This variant has been reported in ClinVar as Pathogenic (19 clinical laboratories) and as pathogenic (1 clinical laboratory) and as Pathogenic by ClinGen RASopathy Variant Curation Expert Panel (expert panel).
ClinVar ↗
Functional evidence
03
Functional
OncoKB: Likely Oncogenic
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Gain-of-function; curated oncogenicity label: Likely Oncogenic.
OncoKB ↗
In silico evidence
04
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.803. BayesDel score = 0.289645.
SpliceAI ↗
COSMIC evidence
05
COSMIC
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV55501342, n = 41 times).
COSMIC ↗
Cancer hotspots evidence
06
Cancer hotspots Not found
This variant lies in a statistically significant hotspot.
ResidueV14
Hotspots ↗