NM_000264.5:c.4251C>T is a synonymous variant (p.His1417=) in exon 23 of PTCH1. SpliceAI predicts no splicing impact (max delta 0.00) and REVEL score is 0.27 in the neutral range, consistent with no functional effect.1 The variant is present at very low frequency in population databases: 10/282,784 alleles in gnomAD v2.1 (AF=0.0035%) and 50/1,614,202 alleles in gnomAD v4.1 (AF=0.0031%), with no homozygotes observed.2 ClinVar classifies this variant as Likely benign, supported by 5 independent clinical testing laboratories. No reputable source reports this variant as pathogenic.3 Seven publications were reviewed for variant-specific evidence, including the ACMG/AMP 2015 guidelines (PMID:25741868), Sherloc refinement (PMID:28492532), GeneReviews NBCCS overview (PMID:20301330), and Gorlin syndrome clinical utility gene card (PMID:21304560). None mention NM_000264.5:c.4251C>T specifically.4 Application of ACMG/AMP 2015 generic combination rules: three supporting benign criteria (BP4, BP6, BP7) and one supporting pathogenic criterion (PM2) are met. The preponderance of evidence supports a Likely benign classification.5
PTCH1
Final classification
Likely Benign
PTCH1 c.4251C>T · p.His1417=
PTCH1
NM_000264.5:c.4251C>T is a synonymous variant (p.His1417=) in exon 23 of PTCH1. SpliceAI predicts no splicing impact (max delta 0.00) and REVEL score is 0.27 in the neutral range, consistent with no functional effect.
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, BP4 supporting benign, BP6 supporting benign, BP7 supporting benign; combination = 1 supporting + 3 supporting benign, which maps to Likely Benign.
Classification rationale
PM2
BP4BP6BP7
Likely Benign
PTCH1 c.4251C>T
PM2 + BP4 + BP6 + BP7
→
Likely Benign
1
spliceai ↗revel
4
PMID:25741868 ↗PMID:28492532 ↗PMID:20301330 ↗PMID:21304560 ↗PMID:15604628 ↗PMID:26389258 ↗PMID:26389333 ↗
5
generic_acmg_combination_rules
Gene diagram
· NM_000264.5 · variants mapped to exon structure
PTCH1
NM_000264.5
Fetching transcript structure from UCSC…
Applied criteria · 4 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
Research & evidence
Population frequency · supports benign
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 3.09751e-05; MAF= 0.00310%, 50/1614202 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 3.7287e-05; MAF= 0.00373%, 44/1180036 alleles, homozygotes = 0); grpmax FAF= 2.826e-05.
v2.1
This variant is present in gnomAD v2.1 (AF= 3.53627e-05; MAF= 0.00354%, 10/282784 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 8.46501e-05; MAF= 0.00847%, 3/35440 alleles, homozygotes = 0); grpmax FAF= 1.686e-05.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.0031%
· 50 / 1,614,202
0 hom · FAF 0.0028%
0 hom · FAF 0.0028%
European (non-Finnish) 44 / 1,180,036 |
0.0037% |
Admixed American 2 / 60,032 |
0.0033% |
African/African American 2 / 75,058 |
0.0027% |
South Asian 2 / 91,088 |
0.0022% |
+ 6 not observed (Remaining individuals, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish)
gnomAD v2.1
0.0035%
· 10 / 282,784
0 hom · FAF 0.0017%
0 hom · FAF 0.0017%
Admixed American 3 / 35,440 |
0.0085% |
African/African American 1 / 24,956 |
0.004% |
European (non-Finnish) 5 / 129,106 |
0.0039% |
South Asian 1 / 30,616 |
0.0033% |
+ 4 not observed (Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals)
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Likely benign (5 clinical laboratories). (ClinVarID = 132735)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.27.
Functional
Unknown Oncogenic Effect
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
Triaged references · 7 PMIDs not cited in assessment
25741868 ↗
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
CLINVAR
15604628 ↗
Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors.
CLINVAR
26389258 ↗
Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional Version.
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR