NM_033360.4:c.-11-30T>C is a deep intronic substitution in intron 1 of KRAS, 30 nucleotides upstream of the coding region start. SpliceAI predicts no splice impact (max delta = 0.01), satisfying RASopathy VCEP BP4 (Supporting) for a negligible splicing outcome.1 The variant satisfies RASopathy VCEP BP7 (Supporting) as an intronic variant with no predicted splice impact and evidence of standing variation in gnomAD (8/213,854 alleles in v2.1, predominantly East Asian), indicating the nucleotide is not highly conserved.2 Population frequency in gnomAD (grpmax FAF 0.0228% v2.1) falls below both the BS1 threshold (0.025%) and the BA1 threshold (0.05%), precluding application of benign population-frequency criteria.3 The variant is present in gnomAD, ruling out PM2 (absence from controls). No pathogenic criteria are met.4 No publications, functional data, ClinVar entries, de novo reports, segregation data, or proband-level clinical information exist for this variant.5 Under the RASopathy VCEP v2.3.0 scoring framework, two supporting benign criteria (BP4 + BP7) are met, which satisfies Rule19 (≥2 Supporting Benign criteria) for a classification of Likely Benign.6
KRAS
Final classification
Likely Benign
KRAS c.-11-30T>C · p.?
KRAS
NM_033360.4:c.-11-30T>C is a deep intronic substitution in intron 1 of KRAS, 30 nucleotides upstream of the coding region start.
ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for KRAS Version 2.3.0 v2.3.0 criteria-combination framework: matched Rule19 (Benign.Supporting >=2) with applied criteria: BP4 supporting, BP7 supporting; maps to Likely Benign.
Classification rationale
BP4BP7
Likely Benign
KRAS c.-11-30T>C
BP4 + BP7
→
Likely Benign
Gene diagram
· NM_033360.4 · variants mapped to exon structure
KRAS
NM_033360.4
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 13 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
BP4
supporting
Benign
RASopathy VCEP BP4 (Supporting) applies to splicing variants for which the predicted outcome is negligible. SpliceAI predicts no significant splice impact for NM_033360.4:c.-11-30T>C (max delta score = 0.01), well below any threshold for splice-altering prediction.
SpliceAI max delta = 0.01no donor/acceptor gain or loss predicted.VCEP BP4 rule: splicing predicted outcome is negligible.
✓
BP7
supporting
review
Benign
RASopathy VCEP BP7 (Supporting) applies to intronic positions (excluding canonical splice sites) when splicing prediction algorithms predict no splice impact AND the nucleotide is not highly conserved. This variant resides in intron 1, SpliceAI predicts no splice impact (max delta = 0.01), and the variant is observed in gnomAD (8 alleles in v2.1, predominantly East Asian), consistent with a position that tolerates variation and is not under strong purifying selection.
SpliceAI max delta = 0.01no splice impact predicted.gnomAD v2.1: 8/213
Assessed · not applied
Pathogenic
PS2
No proband-level clinical data, parental testing, or de novo reports are available for this variant.
PS3
No functional data exists for NM_033360.4:c.-11-30T>C.
PS4
No proband count, case-control, or enrichment data are available for this variant.
PM2
RASopathy VCEP PM2 (Supporting) requires the variant to be absent from gnomAD.
PM6
No de novo observation data (assumed or confirmed) are available for this variant.
PP1
No segregation data are available.
PP3
RASopathy VCEP PP3 requires REVEL ≥ 0.7 for missense variants OR a splicing prediction matching the disease mechanism for splicing variants.
Benign
BA1
RASopathy VCEP BA1 requires gnomAD filtering allele frequency ≥ 0.05%.
BS1
RASopathy VCEP BS1 requires gnomAD filtering allele frequency ≥ 0.025%.
BS2
BS2 requires observation in a healthy adult individual for a disorder with full penetrance expected at an early age.
BS4
BS4 requires lack of segregation in affected family members; no family data are available for this variant.
BP2
BP2 requires observation in trans with a pathogenic variant (for dominant disorders) or in cis with a pathogenic variant, or an alternative molecular cause of RASopathy in the same gene.
BP5
BP5 requires an alternative molecular cause of a RASopathy in a different gene, with phenotype consistent with expected severity.
N/A · 13
PVS1 · PS1 · PM1 · PM3 · PM4 · PM5 · PP2 · PP4 · PP5 · BS3 · BP1 · BP3 · BP6
Research & evidence
Population frequency · supports benign
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 7.04492e-06; MAF= 0.00070%, 11/1561408 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000188973; MAF= 0.01890%, 8/42334 alleles, homozygotes = 0); grpmax FAF= 9.393e-05.
v2.1
This variant is present in gnomAD v2.1 (AF= 3.74087e-05; MAF= 0.00374%, 8/213854 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000473805; MAF= 0.04738%, 7/14774 alleles, homozygotes = 0); grpmax FAF= 0.00022756.
🇨🇦 CA
Not available in gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.0007%
· 11 / 1,561,408
0 hom · FAF 0.0094%
0 hom · FAF 0.0094%
East Asian 8 / 42,334 |
0.019% |
South Asian 1 / 85,892 |
0.0012% |
European (non-Finnish) 2 / 1,147,668 |
0.00017% |
+ 7 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, Middle Eastern, Ashkenazi Jewish, African/African American)
gnomAD v2.1
0.0037%
· 8 / 213,854
0 hom · FAF 0.023%
0 hom · FAF 0.023%
East Asian 7 / 14,774 |
0.047% |
South Asian 1 / 24,650 |
0.0041% |
+ 6 not observed (African/African American, Admixed American, Ashkenazi Jewish, European (Finnish), European (non-Finnish), Remaining individuals)
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
Functional
No data
No calibrated functional assay or RNA evidence was identified for this variant.
COSMIC
Somatic evidence
COSMIC
This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant cancer hotspot.
Sources & reference links