NM_000075.4:c.355-1G>A is a canonical splice acceptor variant in intron 3 of CDK4, a gene in which germline loss-of-function variants cause familial melanoma predisposition. PVS1 is applied at very strong strength per ClinGen SVI PVS1 recommendations (PMC6185798) for canonical ±1,2 splice consensus variants in genes with established LoF disease mechanism.1 The variant is absent from gnomAD v2.1 and v4.1 population databases, meeting PM2 at supporting strength.2 SpliceAI predicts strong acceptor loss (max delta 0.99), consistent with the canonical splice disruption captured by PVS1; PP3 is not applied separately per PMC6185798 guidance against double-counting splice prediction evidence.3 Under generic ACMG/AMP 2015 combination rules, PVS1 (very strong) plus PM2 (supporting) yields a point score of 10, reaching the threshold for a pathogenic classification.4
CDK4
Final classification
VUS
CDK4 c.355-1G>A · p.?
CDK4
NM_000075.4:c.355-1G>A is a canonical splice acceptor variant in intron 3 of CDK4, a gene in which germline loss-of-function variants cause familial melanoma predisposition. PVS1 is applied at very strong strength per ClinGen SVI PVS1 recommendations (PMC6185798) for canonical ±1,2 splice consensus variants in genes with established LoF disease mechanism.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PVS1 very strong, PM2 supporting; combination = 1 very strong + 1 supporting, which maps to VUS.
Classification rationale
PVS1PM2
VUS
CDK4 c.355-1G>A
PVS1 + PM2
→
VUS
Gene diagram
· NM_000075.4 · variants mapped to exon structure
CDK4
NM_000075.4
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 17 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PVS1
very strong
Pathogenic
Canonical splice acceptor variant (c.355-1G>A) in intron 3 of CDK4 (MANE select transcript NM_000075.4). CDK4 loss of function is an established disease mechanism for familial melanoma predisposition. Under PMC6185798 (ClinGen SVI PVS1 recommendations), canonical ±1,2 splice consensus variants qualify for full-strength PVS1 when germline LoF is established for the gene. No downgrade factors identified: transcript is MANE select, no evidence of population LoF enrichment in the affected exon, and no evidence the affected exon is biologically irrelevant.
Canonical splice acceptor variant c.355-1G>A at intron 3 of CDK4.CDK4 germline loss of function is established in familial melanoma predisposition.MANE select transcript NM_000075.4.
✓
PM2
supporting
Pathogenic
This variant is absent from gnomAD v2.1 and v4.1 population databases, consistent with a rare pathogenic variant. Under generic ACMG/AMP, absence from population controls with allele frequency below 0.1% supports PM2 at supporting strength.
Absent from gnomAD v2.1 (exomes).Absent from gnomAD v4.1 (exomes).
Assessed · not applied
Pathogenic
PS2
No de novo testing data available for this variant.
PS3
No functional studies have been identified for NM_000075.4:c.355-1G>A.
PS4
No case-control or prevalence data available.
PM6
No de novo data available for this variant.
PP1
No family segregation data available for this variant.
PP3
SpliceAI predicts strong splice disruption (max delta score 0.99, acceptor loss 0.99), but per PMC6185798 guidance, splice-effect prediction evidence should not be double-counted when PVS1 is already applied for the same canonical splice defect.
PP4
No clinical phenotype data available for the individual carrying this variant.
PP5
This variant is absent from ClinVar.
Benign
BA1
Variant is absent from gnomAD v2.1 and v4.1 population databases.
BS1
Variant is absent from gnomAD population databases.
BS2
No data available on observation of this variant in healthy adult controls where the associated disease is expected to be fully penetrant at an early age.
BS3
No functional studies demonstrating no deleterious effect have been identified for NM_000075.4:c.355-1G>A.
BS4
No family segregation data available to evaluate lack of segregation with disease.
BP2
No data available on observation of this variant in trans with a known pathogenic variant in CDK4.
BP4
Multiple lines of computational evidence suggest a deleterious effect.
BP5
No data available on observation of this variant in a case with an alternate molecular basis for disease.
BP6
This variant is absent from ClinVar.
N/A · 6
PS1 · PM1 · PM5 · PP2 · BP1 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.99). BayesDel score = 0.247776.
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