NM_005631.4:c.1886G>C

SMO · NP_005622.1:p.(Arg629Thr) · NM_005631.4

GRCh37: chr7:128851561 G>C · GRCh38: chr7:129211720 G>C

Gene: SMO Transcript: NM_005631.4

Final call

VUS

PM2 supporting

Variant details

Gene

SMO

Transcript

NM_005631.4

Protein

NP_005622.1:p.(Arg629Thr)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_005631.4:c.1886G>C (p.Arg629Thr) in SMO is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases, meeting PM2 at supporting strength.

No additional pathogenic or benign criteria were met. With only one supporting pathogenic criterion (PM2_supporting) and zero benign criteria, the variant is classified as a Variant of Uncertain Significance (VUS) per the ACMG/AMP 2015 guidelines (PMID:25741868).

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	N/A	NM_005631.4:c.1886G>C is a missense variant (p.Arg629Thr) that does not fall into the default generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants per ClinGen SVI PVS1 recommendations (PMC6185798).	pvs1_generic_framework pvs1_variant_assessment
PS1	Not met	No previously established pathogenic variant with the same amino acid change (p.Arg629Thr) has been reported in ClinVar, COSMIC, or the literature.	clinvar
PS2	Not met	No de novo observation with confirmed paternity and maternity is available for this variant.
PS3	Not met	No well-established in vitro or in vivo functional studies supportive of a damaging effect were identified for NM_005631.4:c.1886G>C. OncoKB classifies this variant as 'Unknown Oncogenic Effect' with no variant-specific functional evidence.	oncokb
PS4	Not met	No case-control or cohort data demonstrating significantly increased prevalence of this variant in affected individuals versus controls.
PS5	Not met	This variant has not been reported as pathogenic by a reputable source; it is absent from ClinVar.	clinvar
PM1	Not met	The variant does not lie in a statistically significant mutational hotspot, and no CSPEC/VCEP-defined critical functional domain has been established for SMO.
PM2	Met	NM_005631.4:c.1886G>C (p.Arg629Thr) is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases, meeting PM2 at supporting strength (allele frequency <0.1% in all population cohorts).	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	No same-residue pathogenic missense comparator was identified at Arg629; automated PM5 candidate harvesting found no eligible comparator variants in ClinVar.	pm5_candidates
PM6	Not met	No assumed de novo observation (without confirmation of paternity and maternity) is available for this variant.
PP1	Not met	No co-segregation data in multiple affected family members is available for this variant.
PP2	Not met	SMO is not included in the HCI prior gene list; no gene-specific missense constraint metric is available to support a low rate of benign missense variation. Without a CSPEC/VCEP-defined PP2 rule for SMO, this criterion cannot be applied.
PP3	Not met	Computational evidence is mixed: REVEL score of 0.897 supports a deleterious effect, but BayesDel noAF score of 0.292 does not reach a confidently pathogenic threshold, and SpliceAI predicts no splice impact (max delta = 0.00). Multiple concordant lines of computational evidence are not present.	revel bayesdel spliceai
PP4	Not met	No patient phenotype or family history data specific to a disease with a single genetic etiology are available for assessment.
PP5	Not met	This variant is absent from ClinVar; no reputable source has reported it as pathogenic.	clinvar
BA1	Not met	The variant is absent from gnomAD; allele frequency does not exceed 5%.	gnomad_v2 gnomad_v4
BS1	Not met	The variant is absent from gnomAD; allele frequency does not exceed the expected threshold for the disorder (>0.3% for non-VCEP).	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	No observation of this variant in healthy adult individuals has been reported; the variant is absent from gnomAD.
BS3	Not met	No well-established in vitro or in vivo functional studies showing no damaging effect on protein function or splicing are available for this variant.
BS4	Not met	No segregation data are available to assess lack of segregation with disease in affected family members.
BP1	Not met	SMO is a proto-oncogene in the hedgehog signaling pathway; somatic activating missense variants are well-established in basal cell carcinoma and medulloblastoma. There is no evidence that germline SMO disease is caused exclusively by truncating variants, and no CSPEC/VCEP defines this rule for SMO.
BP2	Not met	No observation of this variant in trans with a pathogenic variant for a fully penetrant dominant disorder.
BP3	N/A	BP3 applies to in-frame insertions/deletions; this variant is a single-nucleotide substitution.
BP4	Not met	Computational evidence does not uniformly suggest no impact: REVEL score of 0.897 predicts a deleterious effect, which contradicts a benign computational consensus.	revel bayesdel spliceai
BP5	Not met	No observation of this variant in a case with an alternate molecular basis for disease has been reported.
BP6	Not met	This variant is absent from ClinVar; no reputable source has reported it as benign.	clinvar
BP7	N/A	BP7 applies to synonymous variants not predicted to affect splicing; this variant is a missense substitution (p.Arg629Thr).
PM3	N/A	PM3 applies to recessive disorders (detected in trans with a pathogenic variant); SMO-associated disease inheritance pattern is not established as recessive.
PM4	N/A	PM4 applies to protein length changes from in-frame deletions/insertions or stop-loss variants; this variant is a single-nucleotide missense substitution.

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.