Variant classification summary

NM_000222.3:c.-14T>A

KIT · NP_000213.1:p.? · NM_000222.3

GRCh37: chr4:55524168 T>A · GRCh38: chr4:54658001 T>A

Gene: KIT Transcript: NM_000222.3

Final call

Benign

BS1 strong BS2 strong BP4 supporting BP6 supporting

Variant details

Gene

KIT

Transcript

NM_000222.3

Protein

NP_000213.1:p.?

gnomAD AF

0.005266897031419124 (v4.1)

ClinVar

Likely benign

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000222.3:c.-14T>A is a 5'UTR substitution in the KIT gene, located 14 nucleotides upstream of the ATG start codon.

2

This variant is present at appreciable frequency in population databases: gnomAD v2.1 allele frequency 0.35% (977/281,098 alleles, 2 homozygotes) and gnomAD v4.1 allele frequency 0.53% (8,496/1,613,094 alleles, 35 homozygotes), with the highest subpopulation frequency of 0.65% in the European (non-Finnish) population (BS1).

3

The observation of 35 homozygous individuals in gnomAD v4.1 is incompatible with a highly penetrant dominant germline disorder such as familial GIST or piebaldism (BS2).

4

SpliceAI predicts no splicing impact (max delta score = 0.00); no computational evidence suggests a deleterious effect (BP4).

5

ClinVar classifies this variant as Likely benign based on submissions from multiple clinical laboratories; 4 of 5 submitters concluded benign or likely benign (BP6).

6

This variant has been reported in COSMIC (COSV55412424) in 2 somatic cancer samples, which is consistent with a benign germline variant occasionally detected in tumor sequencing.

7

No variant-specific functional studies, de novo occurrences, segregation data, or pathogenic assertions from reputable sources were identified for this variant.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Benign classification because either BA1 is met or at least two strong benign criteria are present.

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	This 5'UTR substitution (c.-14T>A) does not fall into any null-variant bucket (nonsense, frameshift, or canonical ±1,2 splice consensus); PVS1 is not applicable per the ClinGen SVI PVS1 decision tree.	pvs1_variant_assessment pvs1_generic_framework
PS1	N/A	PS1 applies to variants at the same amino acid position as a known pathogenic missense change; this is a 5'UTR non-coding variant with no protein consequence.
PS2	Not met	No de novo occurrence data are available for this variant; PS2 requires confirmed de novo status with both maternity and paternity confirmed.
PS3	Not met	No well-established in vitro or in vivo functional studies have been identified for this 5'UTR variant; PS3 requires variant-specific functional evidence demonstrating a damaging effect on the gene or gene product.
PS4	Not met	The variant is present at 0.35–0.53% allele frequency in gnomAD population controls, inconsistent with a rare pathogenic variant; prevalence in affected individuals does not exceed that in the general population.	gnomad_v2 gnomad_v4
PS5	N/A	PS5 relies on pathogenic computational verdict from REVEL (>0.75) or BayesDel (>0.27); no REVEL or BayesDel scores are available for this non-coding 5'UTR variant.
PM1	Not met	This variant is a 5'UTR substitution located upstream of the coding sequence; it does not reside in a known mutational hotspot or critical functional domain of KIT.
PM2	Not met	PM2 requires absence or very low frequency in population databases (<0.1%). This variant is present in gnomAD v2.1 at 0.35% and v4.1 at 0.53%, well above the PM2 threshold.	gnomad_v2 gnomad_v4
PM5	N/A	PM5 requires a different pathogenic missense change at the same amino acid residue; this is a 5'UTR non-coding variant with no protein residue context, confirmed by the automated PM5 candidate harvest.	pm5_candidates
PM6	Not met	No de novo observation has been reported for this variant; PM6 requires a de novo occurrence with maternity and paternity not confirmed.
PP1	Not met	No co-segregation data are available for this variant; PP1 requires co-segregation with disease in multiple affected family members.
PP2	N/A	PP2 applies to missense variants in genes with a low rate of benign missense variation and where missense variants are a common disease mechanism; this is a 5'UTR substitution, not a missense variant.
PP3	Not met	Multiple lines of computational evidence do not support a deleterious effect. SpliceAI delta score is 0.00 (no predicted splicing impact) and no REVEL/BayesDel/HCI scores are available for this non-coding variant.	spliceai
PP4	Not met	No patient phenotype or family history data are available; PP4 requires that the patient's phenotype or family history is highly specific for a disease with a single genetic etiology.
PP5	Not met	Reputable sources (ClinVar) do not report this variant as pathogenic; the ClinVar consensus classification is Likely benign (3 laboratories) with additional submissions of Benign (1) and Uncertain significance (1). No expert panel has asserted pathogenicity.	clinvar
BA1	Not met	BA1 requires allele frequency >1% in any population. The highest observed subpopulation frequency is 0.654% in European (non-Finnish) gnomAD v4.1, which does not reach the 1% threshold.	gnomad_v2 gnomad_v4
BS1	Met	BS1 is met at strong level: allele frequency exceeds the 0.3% threshold in the European (non-Finnish) population. gnomAD v2.1 NFE AF = 0.592% and gnomAD v4.1 NFE AF = 0.654%, both substantially above the expected frequency for rare KIT-related germline disorders (familial GIST, piebaldism).	gnomad_v2 gnomad_v4
BS2	Met	BS2 is met at strong level: 35 homozygotes are observed in gnomAD v4.1 and 2 homozygotes in gnomAD v2.1. The presence of homozygous individuals in a general population database is inconsistent with a highly penetrant dominant germline disorder such as familial GIST or piebaldism, where homozygosity would be expected to be lethal or cause severe early-onset disease.	gnomad_v2 gnomad_v4
BS3	Not met	No well-established in vitro or in vivo functional studies demonstrating no damaging effect on protein function or splicing have been identified for this 5'UTR variant.
BS4	Not met	No co-segregation data are available; BS4 requires lack of segregation with disease in affected family members.
BP1	N/A	BP1 applies to missense variants in genes where primarily truncating variants cause disease; this is a 5'UTR substitution, not a missense variant.
BP2	Not met	No evidence that this variant has been observed in trans with a pathogenic variant or in cis with a pathogenic variant in any individual.
BP4	Met	BP4 is met at supporting level: SpliceAI predicts no splicing impact (max delta score = 0.00) for this 5'UTR variant. No other computational predictors suggest a deleterious effect. Multiple lines of computational evidence support a benign interpretation.	spliceai
BP5	Not met	No evidence that this variant has been observed in a case with an alternate molecular basis for disease; BP5 requires identification of a different confirmed pathogenic variant explaining the phenotype in the same patient.
BP6	Met	BP6 is met at supporting level: ClinVar reports a consensus classification of Likely benign from multiple clinical laboratories (3 Likely benign, 1 Benign, 1 Uncertain significance). Multiple independent submitters using clinical testing methodology have reached a benign or likely benign conclusion.	clinvar
BP7	N/A	BP7 applies to synonymous (silent) variants for which splicing prediction algorithms predict no impact on splicing; this is a 5'UTR substitution, not a synonymous coding variant.

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