Variant classification summary

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

CREBBP · NP_004371.2:p.? · NM_004380.2

GRCh37: chr16:3807809 C>A · GRCh38: chr16:3757808 C>A

Gene: CREBBP Transcript: NM_004380.2

Final call

VUS

PVS1 very strong PM2 supporting

Variant details

Gene

CREBBP

Transcript

NM_004380.2

Protein

NP_004371.2:p.?

gnomAD AF

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

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.

2

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.

3

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.

4

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.

5

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.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

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	Met	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.	pvs1_generic_framework
PS1	Not met	No known pathogenic variant at the same nucleotide position with a different nucleotide change has been identified in ClinVar or the literature.	clinvar
PS2	Not assessed	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.	clinvar
PS3	Not assessed	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.
PS4	Not assessed	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.
PS5	Not met	No reputable source has reported this variant as pathogenic. ClinVar has no entry for NM_004380.2:c.3609+1G>T.	clinvar
PM1	Not met	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.
PM2	Met	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.	gnomad_v2 gnomad_v4
PM5	N/A	PM5 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.
PM6	Not assessed	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.	clinvar
PP1	Not assessed	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.
PP2	N/A	PP2 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.
PP3	Not met	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.	spliceai bayesdel
PP4	Not assessed	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.
PP5	Not met	No reputable source has reported NM_004380.2:c.3609+1G>T as pathogenic. ClinVar has no entry for this variant.	clinvar
BA1	Not met	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%.	gnomad_v2 gnomad_v4
BS1	Not met	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%.	gnomad_v2 gnomad_v4
BS2	Not assessed	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.
BS3	Not met	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.	spliceai
BS4	Not met	BS4 requires lack of segregation in an affected family member. No segregation data of any kind were identified for this variant.
BP1	N/A	BP1 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.
BP2	N/A	BP2 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.
BP3	N/A	BP3 applies to in-frame insertions/deletions in repetitive regions. NM_004380.2:c.3609+1G>T is a substitution, not an in-frame indel.
BP4	Not met	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.	spliceai bayesdel
BP5	N/A	BP5 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.
BP6	N/A	BP6 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.	clinvar
BP7	N/A	BP7 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.	spliceai
PM3	N/A	PM3 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.
PM4	N/A	PM4 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.

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