About SMO
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
SMO c.1886G>C, p.(Arg629Thr)
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.
Words with a dotted underline have a short definition. Hover or tap them.
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: 1
Benign evidence criteria: 0
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
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).
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: PM2 supporting; combination = 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.
gnomAD v4.1
gnomAD v2.1
Population frequency
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. 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 ↗
Functional evidence
Statement recorded
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. SMO, a G-protein coupled receptor, is mutated in various cancers including basal cell carcinoma and medulloblastoma.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
29 criteria with recorded statuses: 1 met · 22 not met · 0 not assessed · 6 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
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).
No criteria match.
Met · 1
PM2 SupportingNM_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). Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (0 alleles).
- Absent from gnomAD v4.1 (0 alleles).
- Absent from gnomAD-Canada v1.0 (0 alleles).
Sources
Not met · 22 · evaluated, threshold not reached
PS1 No previously established pathogenic variant with the same amino acid change (p.Arg629Thr) has been reported in ClinVar, COSMIC, or the literature. Details ▾Hide ▴
Evidence considered
- Variant is absent from ClinVar
- no same-residue pathogenic comparator identified in any database.
Sources
PS2 No de novo observation with confirmed paternity and maternity is available for this variant. Details ▾Hide ▴
Still missing
- No pedigree or de novo testing data available.
PS3 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. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect
- no variant-specific functional data.
Still missing
- No functional studies available for this variant.
Sources
PS4 No case-control or cohort data demonstrating significantly increased prevalence of this variant in affected individuals versus controls. Details ▾Hide ▴
Still missing
- No case-control or cohort studies available.
PM1 The variant does not lie in a statistically significant mutational hotspot, and no CSPEC/VCEP-defined critical functional domain has been established for SMO. Details ▾Hide ▴
Evidence considered
- Hotspot analysis: residue not statistically significant
- exact variant not listed in cancerhotspots.org.
Still missing
- No SMO-specific domain-level constraint data or VCEP-defined critical domains.
PM6 No assumed de novo observation (without confirmation of paternity and maternity) is available for this variant. Details ▾Hide ▴
Still missing
- No de novo data available.
PP1 No co-segregation data in multiple affected family members is available for this variant. Details ▾Hide ▴
Still missing
- No family segregation data available.
PP2 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. Details ▾Hide ▴
Evidence considered
- HCI prior: not found for SMO (gene_not_supported).
Still missing
- No SMO-specific missense constraint data or VCEP PP2 rule.
PP3 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. Details ▾Hide ▴
Evidence considered
- REVEL: 0.897 (supports pathogenicity).
- BayesDel noAF: 0.292 (borderline
- does not clearly support pathogenicity).
- SpliceAI: max delta 0.00 (neutral).
Sources
PP4 No patient phenotype or family history data specific to a disease with a single genetic etiology are available for assessment. Details ▾Hide ▴
Still missing
- No clinical phenotype data provided.
PP5 This variant is absent from ClinVar; no reputable source has reported it as pathogenic. Details ▾Hide ▴
BA1 The variant is absent from gnomAD; allele frequency does not exceed 5%. Details ▾Hide ▴
Evidence considered
- Absent from all gnomAD cohorts
- allele frequency = 0.
Sources
BS1 The variant is absent from gnomAD; allele frequency does not exceed the expected threshold for the disorder (>0.3% for non-VCEP). Details ▾Hide ▴
Evidence considered
- Absent from all gnomAD cohorts
- allele frequency = 0.
Sources
BS2 No observation of this variant in healthy adult individuals has been reported; the variant is absent from gnomAD. Details ▾Hide ▴
Still missing
- No healthy adult observation data.
BS3 No well-established in vitro or in vivo functional studies showing no damaging effect on protein function or splicing are available for this variant. Details ▾Hide ▴
Still missing
- No functional studies available.
BS4 No segregation data are available to assess lack of segregation with disease in affected family members. Details ▾Hide ▴
Still missing
- No family segregation data available.
BP1 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. Details ▾Hide ▴
Evidence considered
- SMO disease mechanism includes both missense (activating somatic) and potential loss-of-function variants
- truncating-only paradigm not established.
BP2 No observation of this variant in trans with a pathogenic variant for a fully penetrant dominant disorder. Details ▾Hide ▴
Still missing
- No phase data available.
BP4 Computational evidence does not uniformly suggest no impact: REVEL score of 0.897 predicts a deleterious effect, which contradicts a benign computational consensus. Details ▾Hide ▴
Evidence considered
- REVEL: 0.897 (predicts damaging).
- BayesDel noAF: 0.292 (borderline neutral).
- SpliceAI: max delta 0.00 (no splice impact).
Sources
BP5 No observation of this variant in a case with an alternate molecular basis for disease has been reported. Details ▾Hide ▴
Still missing
- No alternate-molecular-basis data available.
BP6 This variant is absent from ClinVar; no reputable source has reported it as benign. Details ▾Hide ▴
PS5 This variant has not been reported as pathogenic by a reputable source; it is absent from ClinVar. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no reputable source classification available.
Sources
Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_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). Details ▾Hide ▴
Evidence considered
- Missense variant
- variant_bucket=other
- apply_generic_pvs1_framework=false.
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PM3 N/APM3 applies to recessive disorders (detected in trans with a pathogenic variant); SMO-associated disease inheritance pattern is not established as recessive. Details ▾Hide ▴
No further detail was recorded.
PM4 N/APM4 applies to protein length changes from in-frame deletions/insertions or stop-loss variants; this variant is a single-nucleotide missense substitution. Details ▾Hide ▴
No further detail was recorded.
PM5 N/ANo same-residue pathogenic missense comparator was identified at Arg629; automated PM5 candidate harvesting found no eligible comparator variants in ClinVar. Details ▾Hide ▴
Evidence considered
- PM5 candidate search returned zero same-residue pathogenic comparators
- recommendation level = not_applicable.
Sources
pm5_candidates
BP3 N/ABP3 applies to in-frame insertions/deletions; this variant is a single-nucleotide substitution. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ABP7 applies to synonymous variants not predicted to affect splicing; this variant is a missense substitution (p.Arg629Thr). Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- SMO
- Transcript
- NM_005631.4
- Coding (HGVS c.)
- NM_005631.4:c.1886G>C
- Protein (HGVS p.)
- NP_005622.1:p.(Arg629Thr)
- GRCh38
- chr7:129211720 G>C
- GRCh37
- chr7:128851561 G>C
Gene diagram
Every interpreted variant in SMO, mapped onto the exon structure of NM_005631.4. Select a row to find it on the plot.
SMONM_005631.4
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in SMO
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
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
Other predictors
- REVEL
- 0.897
- BayesDel
- 0.292
How the predictions were used
PP3 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. Details ▾Hide ▴
Evidence considered
- REVEL: 0.897 (supports pathogenicity).
- BayesDel noAF: 0.292 (borderline
- does not clearly support pathogenicity).
- SpliceAI: max delta 0.00 (neutral).
Sources
BP4 Computational evidence does not uniformly suggest no impact: REVEL score of 0.897 predicts a deleterious effect, which contradicts a benign computational consensus. Details ▾Hide ▴
Evidence considered
- REVEL: 0.897 (predicts damaging).
- BayesDel noAF: 0.292 (borderline neutral).
- SpliceAI: max delta 0.00 (no splice impact).
Sources
BP7 N/ABP7 applies to synonymous variants not predicted to affect splicing; this variant is a missense substitution (p.Arg629Thr). Details ▾Hide ▴
No further detail was recorded.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.897. BayesDel score = 0.291989.
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 0.000
Open source ↗
ClinVar
Captured ClinVar source record
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_005631.4%3Ac.1886G%3EC
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/7-128851561-G-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr7-129211720-G-C?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/7-129211720-G-C
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_005631.4%3Ac.1886…
- OncoKB ↗www.oncokb.org/gene/SMO/R629T
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=SMO+c.1886G%3EC
- Cancer hotspots ↗www.cancerhotspots.org/
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 no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.897. BayesDel score = 0.291989.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. SMO, a G-protein coupled receptor, is mutated in various cancers including basal cell carcinoma and medulloblastoma.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.