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CREBBPc.3609+1G>TUncertain significance
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Variant interpretation report

CREBBP c.3609+1G>T, p.?

NM_004380.2:c.3609+1G>T NP_004371.2: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 CREBBP

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

NM_004380.2:c.3609+1G>T is a canonical splice donor (+1) variant in CREBBP, a gene for which loss of function is an established mechanism of Rubinstein-Taybi syndrome (RSTS). Under ClinGen SVI PVS1 recommendations (PMC6185798), canonical splice variants in genes with established LOF disease mechanism receive PVS1 at very strong strength. The affected intron 18 (of 31 exons) is not in a biologically irrelevant distal region and NMD is predicted.

PM2Supporting
PM2 · supporting

NM_004380.2:c.3609+1G>T is absent from gnomAD v2.1 and v4.1 population databases, meeting the PM2 allele frequency threshold (<0.1%) under generic ACMG/AMP 2015 rules.

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
1.000 maximum delta

Recorded SpliceAI maximum delta score: 1.000. 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.

29 criteria with recorded statuses: 2 met · 10 not met · 7 not assessed · 10 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

NM_004380.2:c.3609+1G>T is a canonical splice donor (+1) variant in CREBBP. Loss of function in CREBBP is an established mechanism for Rubinstein-Taybi syndrome (PMID:41153422). Under ClinGen SVI PVS1 recommendations (PMC6185798), canonical splice variants in genes with established LOF disease mechanism are assigned PVS1 at very strong strength.

The variant is absent from gnomAD v2.1 and v4.1 population databases (0 alleles observed), meeting PM2 at supporting strength under the generic ACMG/AMP <0.1% allele frequency threshold.

SpliceAI predicts strong disruption of the canonical splice donor (max delta score = 1.00; donor loss = 1.0, donor gain = 0.84). This in silico evidence is consistent with PVS1 but is not separately scored as PP3 per PMC6185798 guidance to avoid double-counting splice prediction evidence.

No verified clinical observations (de novo status, case counts, co-segregation, or functional data) for this exact variant were identified. ClinVar has no entry. Multiple criteria (PS2, PS3, PS4, PM6, PP1, PP4) could not be assessed due to absence of variant-specific evidence.

Under the generic ACMG/AMP 2015 final classification rules (PMID:25741868), PVS1 (very strong) with PM2 (supporting) does not meet the threshold for Pathogenic (requires ≥2 supporting or 1 moderate + 1 supporting with PVS1) or Likely Pathogenic (requires PVS1 + 1 moderate). The variant is classified as a Variant of Uncertain Significance (VUS). Clinical corroboration through case-level evidence (de novo observation, co-segregation, or functional studies) would be needed to resolve the classification.

Met · 2

PVS1 Very strongNM_004380.2:c.3609+1G>T is a canonical splice donor (+1) variant in CREBBP, a gene for which loss of function is an established mechanism of Rubinstein-Taybi syndrome (RSTS). Under ClinGen SVI PVS1 recommendations (PMC6185798), canonical splice variants in genes with established LOF disease mechanism receive PVS1 at very strong strength. The affected intron 18 (of 31 exons) is not in a biologically irrelevant distal region and NMD is predicted. Details ▾Hide ▴
Evidence considered
  • Canonical +1 splice donor disruption of CREBBP
  • CREBBP loss of function is a well-established mechanism for Rubinstein-Taybi syndrome
  • PMC6185798 canonical splice PVS1 guidance applied
  • No evidence of NMD escape or non-critical exon exclusion
Still missing
  • RNA studies on patient samples would confirm aberrant splicing and NMD
  • NM_004380.3 is a more recent transcript version
  • confirm transcript relevance
Sources
pvs1_generic_framework ↗41153422
PM2 SupportingNM_004380.2:c.3609+1G>T is absent from gnomAD v2.1 and v4.1 population databases, meeting the PM2 allele frequency threshold (<0.1%) under generic ACMG/AMP 2015 rules. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 (exomes
  • 0 alleles observed)
  • Absent from gnomAD v4.1 (exomes
Sources
gnomad_v2 ↗gnomad_v4 ↗

Not met · 10 · evaluated, threshold not reached

PS1 No known pathogenic variant at the same nucleotide position with a different nucleotide change has been identified in ClinVar or the literature. Details ▾Hide ▴
Evidence considered
  • ClinVar query returned no records for any variant at this position
Still missing
  • No pathogenic comparator at the same canonical splice position available
Sources
clinvar ↗
PM1 This variant is not located in a recognized mutational hotspot or critical functional domain without benign variation. Hotspot analysis found no significant residue-level enrichment. Details ▾Hide ▴
Evidence considered
  • Residue significance not established
  • exact variant not listed in hotspot databases
Still missing
  • No CREBBP-specific mutational hotspot database available for canonical splice positions
PP3 Multiple in silico tools support a deleterious effect on splicing (SpliceAI max delta = 1.0, donor loss = 1.0, donor gain = 0.84), and BayesDel score is 0.66. However, per PMC6185798 guidance, PP3 should not be double-counted when the in silico evidence is the same splice prediction evidence already used to support PVS1 for canonical splice variants. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta = 1.0 (DL = 1.0
  • DG = 0.84)
  • BayesDel = 0.66
  • Splice prediction evidence already consumed by PVS1 per PMC6185798
Sources
spliceai ↗bayesdel
PP5 No reputable source has reported NM_004380.2:c.3609+1G>T as pathogenic. ClinVar has no entry for this variant. Details ▾Hide ▴
Evidence considered
  • ClinVar has no entry for this variant
Still missing
  • Variant not reported by any diagnostic laboratory in ClinVar
Sources
clinvar ↗
BA1 NM_004380.2:c.3609+1G>T is absent from gnomAD v2.1 and v4.1. Allele frequency is well below the BA1 threshold of >1%. Details ▾Hide ▴
Evidence considered
  • Allele count = 0 in gnomAD v2.1
  • Allele count = 0 in gnomAD v4.1
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 NM_004380.2:c.3609+1G>T is absent from gnomAD v2.1 and v4.1. Allele frequency is well below the BS1 threshold of >0.3%. Details ▾Hide ▴
Evidence considered
  • Allele count = 0 in gnomAD v2.1
  • Allele count = 0 in gnomAD v4.1
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS3 No functional studies demonstrating a benign effect of NM_004380.2:c.3609+1G>T were identified. SpliceAI predicts strong splice disruption (max delta = 1.0), inconsistent with a benign functional effect. Details ▾Hide ▴
Evidence considered
  • SpliceAI predicts strong deleterious effect (DL = 1.0
  • DG = 0.84)
  • No experimental data supporting normal splicing
Still missing
  • No benign functional assay data available
Sources
spliceai ↗
BS4 BS4 requires lack of segregation in an affected family member. No segregation data of any kind were identified for this variant. Details ▾Hide ▴
Evidence considered
  • No family study data available
Still missing
  • No segregation data available
BP4 Multiple in silico tools predict a deleterious effect: SpliceAI max delta = 1.0 (donor loss = 1.0, donor gain = 0.84) and BayesDel = 0.66 (above typical benign thresholds). No computational evidence supports a benign effect. Details ▾Hide ▴
Evidence considered
  • SpliceAI strongly predicts splice disruption
  • BayesDel = 0.66
  • above benign range
Sources
spliceai ↗bayesdel
PS5 No reputable source has reported this variant as pathogenic. ClinVar has no entry for NM_004380.2:c.3609+1G>T. Details ▾Hide ▴
Evidence considered
  • ClinVar has no entry for this variant
  • no reputable source classification available
Still missing
  • Variant has not been submitted to ClinVar by any clinical laboratory
Sources
clinvar ↗

Not assessed · 7 · no assessment recorded

PS2 De novo observation data could not be verified. The ClinVar scrape returned no records for this variant, and no publications with confirmed de novo status for NM_004380.2:c.3609+1G>T were identified in the case evidence. Details ▾Hide ▴
Evidence considered
  • ClinVar has no entry for this variant
Still missing
  • No verified de novo occurrence data available
  • Exploratory search returned unverified ClinVar variation IDs (1265488
  • 1265489) that could not be confirmed through deterministic scraping
Sources
clinvar ↗
PS3 No functional assay data specific to NM_004380.2:c.3609+1G>T were identified. Exploratory search suggested PMID:24135865 for a similar splice mutation (c.3609+1G>A), but this does not constitute variant-specific functional evidence for c.3609+1G>T. Details ▾Hide ▴
Evidence considered
  • SpliceAI predicts strong splice disruption (max delta 1.0) but predictive algorithms are not functional assay evidence for PS3
Still missing
  • No RT-PCR
  • minigene
  • or RNA-seq data available for this exact variant
  • PS3 requires direct experimental evidence of variant impact on protein function or splicing
PS4 No verified case counts or case-control data for NM_004380.2:c.3609+1G>T were found. Exploratory search referenced unverified claims in PMID:29452430 supplementary tables, but this could not be confirmed through the evidence pipeline. Details ▾Hide ▴
Still missing
  • No verified proband counts available
  • Variant absent from ClinVar
  • limiting PS4 case accumulation
PM6 Assumed de novo data could not be verified. The ClinVar scrape returned no records, and no publications with confirmed de novo status without parental confirmation were identified. Details ▾Hide ▴
Evidence considered
  • ClinVar has no entry for this variant
Still missing
  • No verified assumed de novo observations available
Sources
clinvar ↗
PP1 No verified co-segregation data for NM_004380.2:c.3609+1G>T in affected families were found. Exploratory search referenced an unverified claim in PMID:20083042, but this could not be confirmed through the evidence pipeline. Details ▾Hide ▴
Still missing
  • No verified family studies with segregation analysis available
PP4 No detailed phenotype information for patients carrying NM_004380.2:c.3609+1G>T was available to assess specificity for Rubinstein-Taybi syndrome. ClinVar has no entries, and no case reports with phenotype descriptions were verified. Details ▾Hide ▴
Still missing
  • No patient phenotype data available to assess PP4
BS2 BS2 requires observation of the variant in a healthy adult individual in a pattern inconsistent with disease penetrance (e.g., homozygous in a dominant disorder). This variant is absent from all population databases, providing no opportunity for BS2 assessment. Details ▾Hide ▴
Evidence considered
  • Variant absent from population databases
Still missing
  • No healthy adult observations available for assessment
Not applicable · 10· recorded as not applicable Show reasons ▾Hide reasons ▴
PM3 N/APM3 applies to recessive disorders where the variant is observed in trans with a pathogenic variant. CREBBP-related Rubinstein-Taybi syndrome is an autosomal dominant disorder. Details ▾Hide ▴

No further detail was recorded.

PM4 N/APM4 applies to protein-length changes from in-frame deletions/insertions, stop-loss, or initiation codon variants. NM_004380.2:c.3609+1G>T is a canonical splice donor substitution and does not fit PM4 criteria. Details ▾Hide ▴

No further detail was recorded.

PM5 N/APM5 applies to different missense changes at the same residue. This variant is a canonical splice donor substitution and cannot be assessed under PM5 semantics. No protein residue is defined. Details ▾Hide ▴

No further detail was recorded.

PP2 N/APP2 applies to missense variants in genes with low rate of benign missense variation and where missense is a common mechanism. This variant is a canonical splice donor substitution, not a missense variant. Details ▾Hide ▴

No further detail was recorded.

BP1 N/ABP1 applies to missense variants in genes where a different missense mechanism is the primary cause of disease. NM_004380.2:c.3609+1G>T is a canonical splice donor substitution, not a missense variant. Details ▾Hide ▴

No further detail was recorded.

BP2 N/ABP2 applies to observation of a variant in trans with a pathogenic variant for a fully penetrant dominant disorder. CREBBP-related Rubinstein-Taybi syndrome is an autosomal dominant disorder, and no in trans observations exist. Details ▾Hide ▴
Evidence considered
  • CREBBP-related RSTS is autosomal dominant
  • BP2 generally not applicable to dominant disorders
BP3 N/ABP3 applies to in-frame insertions/deletions in repetitive regions. NM_004380.2:c.3609+1G>T is a substitution, not an in-frame indel. Details ▾Hide ▴

No further detail was recorded.

BP5 N/ABP5 applies to variants found in a case with an alternate molecular basis for disease. No such data are available, and this criterion requires case-level evidence. Details ▾Hide ▴

No further detail was recorded.

BP6 N/ABP6 requires a reputable source to report the variant as benign. ClinVar has no entry for NM_004380.2:c.3609+1G>T; no benign reporting exists. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
Sources
clinvar ↗
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. NM_004380.2:c.3609+1G>T is a canonical splice donor substitution with strong predicted splice impact, not a synonymous variant. Details ▾Hide ▴
Evidence considered
  • Variant is a canonical +1 splice donor with SpliceAI max delta = 1.0
Sources
spliceai ↗

Identifiers

Gene
CREBBP
Transcript
NM_004380.2
Coding (HGVS c.)
NM_004380.2:c.3609+1G>T
Protein (HGVS p.)
NP_004371.2:p.?
GRCh38
chr16:3757808 C>A
GRCh37
chr16:3807809 C>A

Gene diagram

Every interpreted variant in CREBBP, mapped onto the exon structure of NM_004380.2. Select a row to find it on the plot.

CREBBPNM_004380.2
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 0 / 0 alleles AF 0 · 0 homozygotes · FAF 0

By genetic ancestry

gnomAD-Canada

AF 0 · 0 / 0 alleles · 0 hom

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

Open the gnomAD-Canada detail page →

SpliceAI and Pangolin

SpliceAI acceptor lossat -450 bp
0.070
SpliceAI acceptor gainat -48 bp
0.000
SpliceAI donor lossat +1 bp
1.000
SpliceAI donor gainat +75 bp
0.840
Pangolin splice lossmagnitude shown
-0.890
Pangolin splice gain
0.620

Other predictors

REVEL
Not available
BayesDel
0.660

How the predictions were used

PP3 Multiple in silico tools support a deleterious effect on splicing (SpliceAI max delta = 1.0, donor loss = 1.0, donor gain = 0.84), and BayesDel score is 0.66. However, per PMC6185798 guidance, PP3 should not be double-counted when the in silico evidence is the same splice prediction evidence already used to support PVS1 for canonical splice variants. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta = 1.0 (DL = 1.0
  • DG = 0.84)
  • BayesDel = 0.66
  • Splice prediction evidence already consumed by PVS1 per PMC6185798
Sources
spliceai ↗bayesdel
BP4 Multiple in silico tools predict a deleterious effect: SpliceAI max delta = 1.0 (donor loss = 1.0, donor gain = 0.84) and BayesDel = 0.66 (above typical benign thresholds). No computational evidence supports a benign effect. Details ▾Hide ▴
Evidence considered
  • SpliceAI strongly predicts splice disruption
  • BayesDel = 0.66
  • above benign range
Sources
spliceai ↗bayesdel
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. NM_004380.2:c.3609+1G>T is a canonical splice donor substitution with strong predicted splice impact, not a synonymous variant. Details ▾Hide ▴
Evidence considered
  • Variant is a canonical +1 splice donor with SpliceAI max delta = 1.0
Sources
spliceai ↗

Statement

In silico

SpliceAI predicts possible splice impact for this variant (max delta score = 1.00). BayesDel score = 0.66.

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 1.000 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.

ClinVar

This variant is absent from ClinVar.

In silico

SpliceAI predicts possible splice impact for this variant (max delta score = 1.00). BayesDel score = 0.66.

Somatic

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