NM_000264.5:c.4251C>T

PTCH1 · NP_000255.2:p.(His1417=) · NM_000264.5

GRCh37: chr9:98209287 G>A · GRCh38: chr9:95447005 G>A

Gene: PTCH1 Transcript: NM_000264.5

Final call

Likely Benign

PM2 supporting BP4 supporting benign BP6 supporting benign BP7 supporting benign

Variant details

Gene

PTCH1

Transcript

NM_000264.5

Protein

NP_000255.2:p.(His1417=)

gnomAD AF

3.097505764458228e-05 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

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.

ClinVar classifies this variant as Likely benign, supported by 5 independent clinical testing laboratories. No reputable source reports this variant as pathogenic.

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.

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.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Benign classification because either one strong benign criterion plus one supporting benign criterion, or at least two supporting benign criteria, are present.

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_000264.5:c.4251C>T is a synonymous variant (p.His1417=) in exon 23. It does not fall into any PVS1 null-variant bucket (nonsense, frameshift, canonical splice ±1,2, initiation codon, single/multi-exon deletion). PVS1 decision algorithm does not trigger for synonymous variants.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework
PS1	N/A	Synonymous variant with no amino acid change. PS1 requires the same amino acid change as a previously established pathogenic variant. Not applicable for synonymous changes.
PS2	Not assessed	No de novo data are available for NM_000264.5:c.4251C>T. No publications or ClinVar submissions report de novo occurrence for this variant.
PS3	Not assessed	No variant-specific functional studies were identified for NM_000264.5:c.4251C>T. PMID:25741868 (ACMG guidelines) was reviewed as the sole PS3-candidate paper but does not contain any variant-specific functional data.
PS4	Not assessed	No variant-specific case-control or cohort prevalence data were identified. All PS4-candidate papers (PMID:15604628, 20301330, 21304560, 25741868, 26389258, 26389333, 28492532) are general guidelines or gene-level reviews that do not report variant-specific prevalence statistics.
PS5	Not met	PS5 requires a reputable source to report the variant as pathogenic. ClinVar classifies NM_000264.5:c.4251C>T as Likely benign (5 clinical laboratories, ClinVar ID 132735). No source asserts pathogenicity for this variant.	clinvar
PM1	Not assessed	Residue p.His1417 is not located in a statistically significant mutational hotspot (evidence_brief confirms hotspot analysis negative). No established critical functional domain encompasses this position. Insufficient evidence to invoke PM1.
PM2	Met	NM_000264.5:c.4251C>T is present at extremely low frequency in population databases, below the 0.1% PM2 threshold for non-VCEP generic ACMG. gnomAD v2.1: 10/282,784 alleles (AF=0.0035%); gnomAD v4.1: 50/1,614,202 alleles (AF=0.0031%); gnomAD-Canada: 0 alleles. No homozygotes observed.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	NM_000264.5:c.4251C>T is a synonymous variant (p.His1417=) with no amino acid change. PM5 requires a different pathogenic missense change at the same residue. No missense comparator candidates were identified, and PM5 semantics cannot be applied to a synonymous change.	pm5_candidates
PM6	Not assessed	No de novo data are available for NM_000264.5:c.4251C>T. No publications or ClinVar submissions report de novo occurrence for this variant.
PP1	Not assessed	No co-segregation data are available for NM_000264.5:c.4251C>T. No family studies or segregation analyses were identified in the literature or ClinVar submissions.
PP2	N/A	PP2 applies to missense variants in genes where missense variation is an established disease mechanism and benign missense variation is rare. NM_000264.5:c.4251C>T is a synonymous variant (p.His1417=), not a missense change.
PP3	Not met	In silico predictors do not support a deleterious effect. REVEL score is 0.27 (neutral range, below typical pathogenic threshold of 0.5). SpliceAI max delta score is 0.00 (no splicing impact predicted). No computational evidence supports pathogenicity.	revel spliceai
PP4	Not assessed	No patient phenotype or family history data were provided for assessment. PP4 requires that the patient's phenotype or family history is highly specific for the gene/disease.
PP5	Not met	PP5 requires a reputable source to report the variant as pathogenic. ClinVar classifies NM_000264.5:c.4251C>T as Likely benign from 5 clinical laboratories. No expert panel or reputable source has classified this variant as pathogenic. All reviewed publications are general guidelines or gene-level reviews that do not assert pathogenicity for this variant.	clinvar
BA1	Not met	Allele frequency in gnomAD is far below the 1% BA1 threshold. gnomAD v2.1 AF=0.00354% (10/282,784); gnomAD v4.1 AF=0.00310% (50/1,614,202). BA1 requires allele frequency >1% in any population.	gnomad_v2 gnomad_v4
BS1	Not met	Allele frequency is below the 0.3% BS1 threshold for non-VCEP generic ACMG. Maximum population AF is 0.00847% in Admixed American population (gnomAD v2.1). Does not meet BS1.	gnomad_v2 gnomad_v4
BS2	Not assessed	No specific evidence of observation in healthy adults beyond population database allele counts. BS2 requires documented observation in a healthy adult individual with full penetrance expected at an early age. No such clinical reports were identified.
BS3	Not assessed	No variant-specific functional studies were identified for NM_000264.5:c.4251C>T demonstrating no damaging effect. PMID:25741868 was reviewed as the sole BS3-candidate paper but does not contain any variant-specific functional data.
BS4	Not assessed	No non-segregation data are available for NM_000264.5:c.4251C>T. No family studies demonstrating lack of segregation with disease were identified.
BP1	N/A	BP1 applies to missense variants in genes where truncating variants are a known disease mechanism. NM_000264.5:c.4251C>T is a synonymous variant (p.His1417=), not a missense change.
BP2	Not assessed	No data are available on observation of NM_000264.5:c.4251C>T in trans with a known pathogenic PTCH1 variant. No such observations were reported in ClinVar or the literature.
BP3	N/A	Skipped per adjudication instructions: variant type is substitution (not in-frame indel).
BP4	Met	Multiple lines of computational evidence suggest no impact on the gene product. SpliceAI predicts no splicing alteration (max delta score 0.00). REVEL score is 0.27, in the neutral range. The variant is synonymous (p.His1417=) with no predicted effect on splicing or protein function.	revel spliceai
BP5	Not assessed	No evidence of an alternate molecular basis for disease was identified in the case. BP5 requires that an alternative causative variant has been identified in the patient. No such data were provided.
BP6	Met	ClinVar classifies NM_000264.5:c.4251C>T as Likely benign, supported by 5 clinical laboratories (Ambry Genetics, Invitae/Labcorp, Copenhagen University Hospital, PreventionGenetics, CeGaT). Multiple reputable clinical testing laboratories have independently reached a benign interpretation.	clinvar
BP7	Met	NM_000264.5:c.4251C>T is a synonymous variant (p.His1417=) in exon 23. SpliceAI predicts no splicing impact (max delta 0.00). The nucleotide is not located at a highly conserved position predicted to affect splicing. BP7 is met for a synonymous variant with no predicted splice effect.	spliceai

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.