NM_007217.3:c.345T>G

PDCD10 · NP_009148.2:p.(Ser115Arg) · NM_007217.3

GRCh37: chr3:167413434 A>C · GRCh38: chr3:167695646 A>C

Gene: PDCD10 Transcript: NM_007217.3

Final call

VUS

PM2 supporting

Variant details

Gene

PDCD10

Transcript

NM_007217.3

Protein

NP_009148.2:p.(Ser115Arg)

gnomAD AF

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_007217.3:c.345T>G (p.Ser115Arg) in PDCD10 is absent from all population databases (gnomAD v2.1, v4.1, and gnomAD-Canada), meeting PM2 at a supporting level.

The only criterion met is PM2 (supporting); no other pathogenic or benign criteria are satisfied. According to the generic ACMG/AMP 2015 combination rules (PMID:25741868), a single supporting criterion is insufficient for classification as likely pathogenic or likely benign. The variant remains a variant of uncertain significance (VUS).

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	Not met	NM_007217.3:c.345T>G is a missense variant (p.Ser115Arg) in exon 6 of PDCD10. It does not fall into any of the generic PVS1 null-variant buckets — it is neither a nonsense/frameshift variant nor a canonical ±1,2 splice consensus alteration. The ClinGen SVI PVS1 framework (PMC6185798) therefore does not support PVS1 application for this variant class, even though PDCD10 loss of function is an established disease mechanism for familial cerebral cavernous malformations.	pvs1_variant_assessment pvs1_gene_context pvs1_generic_framework
PS1	Not met	No previously established pathogenic variant with the same amino acid change (p.Ser115Arg) at this position has been reported in ClinVar or the literature. This variant is absent from ClinVar entirely.	clinvar
PS2	Not met	No de novo observation with confirmed paternity and maternity has been reported for this variant. No publications describing this variant were identified.
PS3	Not met	No well-established functional studies demonstrating a damaging effect for NM_007217.3:c.345T>G (p.Ser115Arg) have been identified. The literature search returned no publications mentioning this variant. The five PDCD10/CCM3 functional papers reviewed describe gene-level LoF effects (siRNA silencing, autophagy defects, DLL4-Notch signaling) but do not test or report this specific missense change.
PS4	Not met	No case-control or cohort data demonstrate enrichment of this variant in affected individuals compared to controls. The variant is absent from ClinVar and has not been reported in any publication.	clinvar
PS5	Not met	Not supported by evidence. The variant is not located in a statistically significant mutational hot spot per cancerhotspots.org. No evidence places this residue in a critical functional domain with an absence of benign variation.
PM1	Not met	Residue Ser115 is not located in a statistically significant mutational hotspot per cancerhotspots.org. No domain-specific constraint or ClinGen expert-curated domain data are available for PDCD10 to support PM1.
PM2	Met	NM_007217.3:c.345T>G is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 (allele frequency = 0.0), well below the 0.1% threshold for a rare variant in a gene associated with autosomal dominant familial cerebral cavernous malformations. Absence from large population databases supports pathogenicity at a supporting level.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not met	No comparator missense variants at residue Ser115 have been identified as pathogenic in ClinVar. The PM5 candidate search found zero same-residue candidates. A different pathogenic missense at the same position has not been established.	pm5_candidates
PM6	Not met	No assumed de novo observation (without confirmed paternity/maternity) has been reported for this variant.
PP1	Not met	No cosegregation data with disease in multiple affected family members has been reported for this variant.
PP2	Not met	HCI prior probability data is not available for PDCD10. Without quantitative evidence that PDCD10 has a low rate of benign missense variation, PP2 cannot be applied.
PP3	Not met	Computational evidence is inconsistent and does not provide multiple lines of support for a deleterious effect. REVEL score is 0.649 (borderline, not strongly pathogenic), BayesDel score is 0.175 (benign range), and SpliceAI predicts no splice impact (max delta = 0.02). The in silico predictions do not converge on a damaging effect.	revel bayesdel spliceai
PP4	Not met	No patient phenotype or family history data are available for this case. PP4 requires a phenotype highly specific for a disease with a single genetic etiology, which cannot be assessed without clinical context.
PP5	Not met	No reputable source (ClinVar submitter, clinical laboratory, or publication) has reported this variant as pathogenic. The variant is entirely absent from ClinVar and the published literature.	clinvar
BA1	Not met	The variant is absent from all gnomAD population databases (allele frequency = 0.0), far below the 1% BA1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	The variant is absent from all gnomAD population databases (allele frequency = 0.0), far below the 0.3% BS1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	No observation of this variant in a healthy adult individual has been reported. The variant is absent from all population databases and has not been reported in any publication.
BS3	Not met	No well-established functional studies demonstrating a benign effect for p.Ser115Arg have been identified. While BayesDel (0.175) and SpliceAI (max delta 0.02) suggest no strong deleterious impact, REVEL (0.649) remains in a borderline range, preventing a confident BS3 determination.	revel bayesdel spliceai
BS4	Not met	No segregation data are available to demonstrate lack of segregation with disease in affected family members.
BP1	Not met	While PDCD10 loss of function is an established mechanism for familial cerebral cavernous malformations, there is insufficient evidence to conclude that primarily truncating variants cause disease to the exclusion of missense variants. The GeneReviews entry and supporting literature describe heterozygous germline pathogenic variants broadly without specifying that missense variants are not a disease mechanism. BP1 cannot be applied without explicit evidence that missense variants in PDCD10 are not pathogenic.	pvs1_gene_context
BP2	Not met	No phasing data are available to determine whether this variant has been observed in trans with a pathogenic variant in PDCD10 (autosomal dominant FCCM) or in cis with a pathogenic variant.
BP4	Not met	Multiple lines of computational evidence do not uniformly suggest no impact. While BayesDel (0.175, benign range) and SpliceAI (max delta 0.02, no splicing impact) are consistent with a benign interpretation, REVEL (0.649) remains in a borderline range that does not confidently exclude a deleterious effect. The evidence is mixed rather than convergent on benign.	revel bayesdel spliceai
BP5	Not met	No evidence that this variant has been observed in a case with an alternate molecular basis for disease.
BP6	Not met	No reputable source has reported this variant as benign. The variant is absent from ClinVar and the published literature.	clinvar
BP7	N/A	BP7 applies to synonymous variants with no predicted splice impact. NM_007217.3:c.345T>G is a missense variant (p.Ser115Arg), not a synonymous change.
BP3	N/A	BP3 applies to in-frame insertions/deletions in repetitive regions. This variant is a single-nucleotide substitution.
PM3	N/A	PM3 applies to recessive disorders where a variant is observed in trans with a pathogenic variant. PDCD10-associated familial cerebral cavernous malformations follow autosomal dominant inheritance.
PM4	N/A	PM4 applies to protein length changes from in-frame deletions/insertions or stop-loss variants. This variant is a missense substitution that does not alter protein length.

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.