Variant classification summary

NM_033360.4:c.-11-30T>C

KRAS · NP_203524.1:p.? · NM_033360.4

GRCh37: chr12:25398359 A>G · GRCh38: chr12:25245425 A>G

Gene: KRAS Transcript: NM_033360.4

Final call

Likely Benign

BP4 supporting BP7 supporting

Variant details

Gene

KRAS

Transcript

NM_033360.4

Protein

NP_203524.1:p.?

gnomAD AF

7.04492355617494e-06 (v4.1)

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

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.

2

SpliceAI predicts no splice impact (max delta = 0.01), satisfying RASopathy VCEP BP4 (Supporting) for a negligible splicing outcome.

3

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.

4

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.

5

The variant is present in gnomAD, ruling out PM2 (absence from controls). No pathogenic criteria are met.

6

No publications, functional data, ClinVar entries, de novo reports, segregation data, or proband-level clinical information exist for this variant.

7

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.

Final determination: Rule19 in the ClinGen RASopathy Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for KRAS Version 2.3.0 v2.3.0 criteria-combination framework is satisfied by the adjudicated criteria, so the variant is classified as Likely Benign.

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	RASopathy VCEP v2.3.0 designates PVS1 as not applicable for KRAS; the variant NM_033360.4:c.-11-30T>C is a deep intronic substitution and does not fall into any null-variant bucket (nonsense, frameshift, canonical splice site).	cspec
PS1	N/A	PS1 requires same amino acid change as a previously established pathogenic variant; NM_033360.4:c.-11-30T>C is a deep intronic substitution with no amino acid consequence.	cspec
PS2	Not assessed	No proband-level clinical data, parental testing, or de novo reports are available for this variant. Cannot evaluate PS2 without confirmed de novo occurrence in a RASopathy-affected individual.
PS3	Not met	No functional data exists for NM_033360.4:c.-11-30T>C. A comprehensive literature search returned zero publications; the variant has not been tested in any VCEP-approved functional assay (RAS activation, MEK/ERK activation). The variant is deep intronic and falls outside the range of any systematically characterized functional domain.
PS4	Not assessed	No proband count, case-control, or enrichment data are available for this variant. RASopathy VCEP PS4 is point-based and requires proband phenotypes; none are provided.
PM1	N/A	RASopathy VCEP PM1 applies only to critical functional domains (P-loop AA 10-17, Switch I AA 25-40, Switch II AA 57-64, SAK AA 145-156). NM_033360.4:c.-11-30T>C is a deep intronic variant in intron 1, upstream of all coding sequence, and does not reside within any recognized functional domain.	cspec vcep_alignment_with_pm1_domains_pptx
PM2	Not met	RASopathy VCEP PM2 (Supporting) requires the variant to be absent from gnomAD. NM_033360.4:c.-11-30T>C is present in gnomAD v2.1 at 8/213,854 alleles (AF = 0.00374%; grpmax FAF = 0.0228%) and in gnomAD v4.1 at 11/1,561,408 alleles (AF = 0.00070%). The variant is not absent, so PM2 is not satisfied.	gnomad_v2 gnomad_v4
PM5	N/A	PM5 requires a novel missense change at a codon where a different pathogenic missense has been established. NM_033360.4:c.-11-30T>C is a deep intronic substitution with no amino acid consequence; PM5 is not applicable.	cspec pm5_candidates
PM6	Not assessed	No de novo observation data (assumed or confirmed) are available for this variant. PM6 requires a de novo occurrence in a proband; none is reported in the literature or provided clinically.
PP1	Not assessed	No segregation data are available. RASopathy VCEP PP1 requires ≥3 informative meioses for Supporting strength; no family studies have been reported for this variant.
PP2	N/A	RASopathy VCEP designates PP2 as not applicable because the KRAS missense z-score in gnomAD is <3.09.	cspec
PP3	Not met	RASopathy VCEP PP3 requires REVEL ≥ 0.7 for missense variants OR a splicing prediction matching the disease mechanism for splicing variants. REVEL is unavailable (intronic variant). SpliceAI predicts no significant splice impact (max delta = 0.01); thus the computational evidence does not support a deleterious effect.	spliceai cspec
PP4	N/A	RASopathy VCEP designates PP4 as not applicable; phenotype specificity is addressed through PS4 scoring.	cspec
PP5	N/A	PP5 is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee; the RASopathy VCEP explicitly marks it as not applicable.	cspec
BA1	Not met	RASopathy VCEP BA1 requires gnomAD filtering allele frequency ≥ 0.05%. The grpmax FAF is 0.0228% in v2.1 and 0.00939% in v4.1, both below the 0.05% threshold.	gnomad_v2 gnomad_v4 cspec
BS1	Not met	RASopathy VCEP BS1 requires gnomAD filtering allele frequency ≥ 0.025%. The grpmax FAF is 0.0228% in v2.1, narrowly below the threshold; v4.1 grpmax FAF is 0.00939%, also below.	gnomad_v2 gnomad_v4 cspec
BS2	Not assessed	BS2 requires observation in a healthy adult individual for a disorder with full penetrance expected at an early age. No such observation data are available for this variant.
BS3	N/A	RASopathy VCEP designates BS3 as not applicable.	cspec
BS4	Not assessed	BS4 requires lack of segregation in affected family members; no family data are available for this variant.
BP1	N/A	RASopathy VCEP BP1 applies specifically to truncating variants (nonsense, frameshift, canonical splice, initiation codon, exon deletion) in genes where the disease mechanism is gain-of-function. NM_033360.4:c.-11-30T>C is a deep intronic substitution and is not a truncating variant.	cspec
BP2	Not assessed	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. No such data are available.
BP4	Met	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 cspec
BP5	Not assessed	BP5 requires an alternative molecular cause of a RASopathy in a different gene, with phenotype consistent with expected severity. No such data are available.
BP6	N/A	BP6 is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee; the RASopathy VCEP explicitly marks it as not applicable.	cspec
BP7	Met	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 gnomad_v2 cspec
BP3	N/A	Pre-determined skip: RASopathy VCEP designates BP3 as not applicable (no known benign repetitive areas in RASopathy genes).
PM3	N/A	Pre-determined skip: RASopathies are autosomal dominant; PM3 (recessive, detected in trans) is not applicable.
PM4	N/A	Pre-determined skip: PM4 applies to in-frame deletions/insertions or stop-loss variants. NM_033360.4:c.-11-30T>C is an intronic substitution, not a protein-length-altering variant.

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