0%
CDK4c.355-1G>AUncertain significance
Print report
Variant interpretation report

CDK4 c.355-1G>A, p.?

NM_000075.4:c.355-1G>A NP_000066.1:p.? View identifiers
Classification
Uncertain significance

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.

Uncertain.The recorded classification is uncertain significance.

In plain language

Gene-level background from the recorded interpretation.

About CDK4

No gene-level summary was recorded for this case.

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.
01The reasoning

How it was classified

The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 2 Benign evidence criteria: 0
Pathogenic criteria applied · 2
PVS1Very strong
PVS1 · very strong

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.

PM2Supporting
PM2 · supporting

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.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Uncertain significance

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.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

SpliceAI score
0.990 maximum delta

Recorded SpliceAI maximum delta score: 0.990. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗
No screenshot for this evidence
Functional evidence
Not recorded

No standalone functional evidence summary is recorded in evidence_summary.functional.

No listed criterion applied OncoKB ↗
Somatic evidence
No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Context only COSMIC ↗
For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

26 criteria with recorded statuses: 2 met · 8 not met · 10 not assessed · 6 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP4BP5BP6BP7
Met Not met Not assessed Not applicable

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.

The variant is absent from gnomAD v2.1 and v4.1 population databases, meeting PM2 at supporting strength.

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.

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.

Met · 2

PVS1 Very strongCanonical 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. Details ▾Hide ▴
Evidence considered
  • 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.
  • ClinGen SVI PVS1 recommendation PMC6185798: canonical ±1
  • 2 splice variants qualify for PVS1.
Sources
pvs1_generic_framework ↗
PM2 SupportingThis 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. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 (exomes).
  • Absent from gnomAD v4.1 (exomes).
Sources
gnomad_v2 ↗gnomad_v4 ↗

Not met · 8 · evaluated, threshold not reached

PS3 No functional studies have been identified for NM_000075.4:c.355-1G>A. The literature search yielded no publications with variant-specific functional data, and no systematically characterized range including this splice position was found in any study. Details ▾Hide ▴
Still missing
  • No functional studies identified 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. BayesDel score of 0.247776 does not reach a standard pathogenic threshold for non-splice in silico evidence. No additional independent in silico pathogenic evidence is available. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta 0.99 (acceptor loss) — splice prediction already captured by PVS1 per PMC6185798.
  • BayesDel score 0.247776 — below standard pathogenic threshold.
Still missing
  • No independent in silico pathogenic evidence beyond splice prediction already captured by PVS1.
Sources
spliceai ↗bayesdel
PP5 This variant is absent from ClinVar. No expert panel or reputable source has classified it as pathogenic or likely pathogenic. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar.
Sources
clinvar ↗
BA1 Variant is absent from gnomAD v2.1 and v4.1 population databases. Allele frequency does not exceed the 1% BA1 threshold for a benign stand-alone criterion. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD population databases (allele frequency = 0).
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 Variant is absent from gnomAD population databases. Allele frequency does not exceed the 0.3% BS1 threshold for a strong benign criterion. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD population databases (allele frequency = 0).
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS3 No functional studies demonstrating no deleterious effect have been identified for NM_000075.4:c.355-1G>A. The literature search yielded no publications with variant-specific functional data. Details ▾Hide ▴
Still missing
  • No functional studies demonstrating benign effect identified.
BP4 Multiple lines of computational evidence suggest a deleterious effect. SpliceAI predicts strong splice disruption (max delta score 0.99, acceptor loss 0.99). BayesDel score of 0.247776 does not support a benign classification. BP4 requires multiple lines of computational evidence suggesting no impact. Details ▾Hide ▴
Evidence considered
  • SpliceAI predicts strong acceptor loss (delta 0.99).
  • BayesDel score 0.247776 — does not clearly support benign classification.
Sources
spliceai ↗bayesdel
BP6 This variant is absent from ClinVar. No reputable source has classified it as benign or likely benign. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar.
Sources
clinvar ↗

Not assessed · 10 · no assessment recorded

PS2 No de novo testing data available for this variant. Details ▾Hide ▴
Still missing
  • No de novo testing data or parental studies available.
PS4 No case-control or prevalence data available. The variant is absent from ClinVar and no published case observations were identified in the literature search. Details ▾Hide ▴
Still missing
  • No case observations or case-control studies available.
PM6 No de novo data available for this variant. Details ▾Hide ▴
Still missing
  • No de novo testing data available.
PP1 No family segregation data available for this variant. Details ▾Hide ▴
Still missing
  • No co-segregation studies or family data available.
PP4 No clinical phenotype data available for the individual carrying this variant. PP4 requires that the patient's phenotype or family history is highly specific for the disease associated with the gene. Details ▾Hide ▴
Still missing
  • No proband phenotype information available.
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. Absence from gnomAD alone does not satisfy BS2. Details ▾Hide ▴
Still missing
  • No data on healthy adult carriers beyond population databases.
BS4 No family segregation data available to evaluate lack of segregation with disease. Details ▾Hide ▴
Still missing
  • No family segregation data available.
BP2 No data available on observation of this variant in trans with a known pathogenic variant in CDK4. Details ▾Hide ▴
Still missing
  • No phase data available.
BP5 No data available on observation of this variant in a case with an alternate molecular basis for disease. Details ▾Hide ▴
Still missing
  • No data on cases with alternate molecular cause.
PS5 No data on independently verified pathogenic nucleotide variants at the c.355-1 position in CDK4. The variant is a splice site change; no comparator nucleotide substitutions at this exact intronic position were identified in ClinVar. Details ▾Hide ▴
Still missing
  • No comparator pathogenic variants at c.355-1 identified.
Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 applies when the same amino acid change is produced by a different nucleotide substitution previously established as pathogenic. This is a canonical splice site variant producing an unknown protein consequence (p.?); no applicable amino acid-level comparison. Details ▾Hide ▴

No further detail was recorded.

PM1 N/APM1 applies to missense variants located in a critical functional domain or mutational hotspot. This is a canonical splice site variant; it does not alter a specific amino acid residue within a domain. Domain-level impact of the splice defect is captured by PVS1. Details ▾Hide ▴

No further detail was recorded.

PM5 N/APM5 requires a same-residue missense change already classified as pathogenic. This is a canonical splice site variant producing an unknown protein consequence (p.?); no residue-level comparison is possible. pm5_candidates.json confirms no eligible comparator candidates. Details ▾Hide ▴

No further detail was recorded.

PP2 N/APP2 applies to missense variants in genes with a low rate of benign missense variation and high missense constraint (high Z-score). This is a canonical splice site variant, not a missense change. Details ▾Hide ▴

No further detail was recorded.

BP1 N/ABP1 applies to missense variants in genes where only truncating variants cause disease. This is a canonical splice site variant expected to produce a truncating effect via aberrant splicing or NMD, not a missense change. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ABP7 applies to silent/synonymous variants with no predicted splice impact. This is a canonical splice site variant with a SpliceAI max delta score of 0.99, predicting strong splice disruption. Not applicable. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene
CDK4
Transcript
NM_000075.4
Coding (HGVS c.)
NM_000075.4:c.355-1G>A
Protein (HGVS p.)
NP_000066.1:p.?
GRCh38
chr12:57751091 C>T
GRCh37
chr12:58144874 C>T

Gene diagram

Every interpreted variant in CDK4, mapped onto the exon structure of NM_000075.4. Select a row to find it on the plot.

CDK4NM_000075.4
Fetching transcript structure from UCSC…
gnomAD v4.1 Allele count data not recorded
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat -1 bp
0.990
SpliceAI acceptor gainat -2 bp
0.690
SpliceAI donor lossat -168 bp
0.020
SpliceAI donor gainat -407 bp
0.010
Pangolin splice lossmagnitude shown
-0.880
Pangolin splice gain
0.540

Other predictors

REVEL
Not available
BayesDel
0.248

How the predictions were used

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. BayesDel score of 0.247776 does not reach a standard pathogenic threshold for non-splice in silico evidence. No additional independent in silico pathogenic evidence is available. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta 0.99 (acceptor loss) — splice prediction already captured by PVS1 per PMC6185798.
  • BayesDel score 0.247776 — below standard pathogenic threshold.
Still missing
  • No independent in silico pathogenic evidence beyond splice prediction already captured by PVS1.
Sources
spliceai ↗bayesdel
BP4 Multiple lines of computational evidence suggest a deleterious effect. SpliceAI predicts strong splice disruption (max delta score 0.99, acceptor loss 0.99). BayesDel score of 0.247776 does not support a benign classification. BP4 requires multiple lines of computational evidence suggesting no impact. Details ▾Hide ▴
Evidence considered
  • SpliceAI predicts strong acceptor loss (delta 0.99).
  • BayesDel score 0.247776 — does not clearly support benign classification.
Sources
spliceai ↗bayesdel
BP7 N/ABP7 applies to silent/synonymous variants with no predicted splice impact. This is a canonical splice site variant with a SpliceAI max delta score of 0.99, predicting strong splice disruption. Not applicable. Details ▾Hide ▴

No further detail was recorded.

Statement

In silico

SpliceAI predicts possible splice impact for this variant (max delta score = 0.99). BayesDel score = 0.247776.

0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 Captured gnomAD v4.1 source record Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.990 Open source ↗
ClinVar Captured ClinVar source record Open source ↗
COSMIC Captured COSMIC source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant is absent from ClinVar.

In silico

SpliceAI predicts possible splice impact for this variant (max delta score = 0.99). BayesDel score = 0.247776.

Somatic

This variant has not previously been reported in somatic cancers (COSMIC).