NM_000264.5:c.-9_-4del

PTCH1 · NP_000255.2:p.? · NM_000264.5

GRCh37: chr9:98270646 TGCCGCC>T · GRCh38: chr9:95508364 TGCCGCC>T

Gene: PTCH1 Transcript: NM_000264.5

Final call

Benign

BA1 stand-alone benign BS1 strong benign

Variant details

Gene

PTCH1

Transcript

NM_000264.5

Protein

NP_000255.2:p.?

gnomAD AF

0.013118005334506558 (v4.1)

ClinVar

Benign

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

The PTCH1 NM_000264.5:c.-9_-4del (NP_000255.2:p.?) variant has been reported in ClinVar, where current submissions classify it as benign or likely benign.

This variant is common in population databases, with an allele frequency of 1.31180% in gnomAD v4.1, 0.75389% in gnomAD v2.1, and 1.26862% in gnomAD-Canada, which is above the non-VCEP BA1 benign threshold of 1%.

In silico splice prediction does not support a splice-disrupting effect, with SpliceAI showing a maximum delta score of 0.01.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Benign classification because either BA1 is met or at least two strong 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	Not met	PTCH1 loss of function is an established disease mechanism, but this 5′ UTR deletion does not fall within the generic PVS1 null-variant categories for nonsense, frameshift, or canonical ±1/2 splice variants, so PVS1 is not supported.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework
PS1	N/A	PS1 is not applicable because this variant is not a protein-coding substitution with an established same-amino-acid pathogenic comparator.
PS2	Not assessed	No confirmed de novo data were identified for this variant.
PS3	Not assessed	No well-established functional studies for this specific variant were identified that demonstrate a damaging effect.	oncokb
PS4	Not met	Available evidence does not show enrichment of this variant in affected individuals, and its population frequency is high for a pathogenic PTCH1 germline allele.	clinvar gnomad_v2 gnomad_v4 gnomad_canada
PM1	N/A	PM1 is not applicable because this variant is in the 5′ UTR and not in an established mutational hotspot or critical functional protein domain without benign variation.
PM2	Not met	This variant is not absent or rare in population databases. Its allele frequency is 1.31180% in gnomAD v4.1, 0.75389% in gnomAD v2.1, and 1.26862% in gnomAD-Canada, which is far above the PM2 rarity threshold of less than 0.1%.	gnomad_v2 gnomad_v4 gnomad_canada
PM3	Not assessed	No evidence was identified showing this variant in trans with a pathogenic variant in a recessive disease context.
PM4	N/A	PM4 is not applicable because this is a 5′ UTR deletion and there is no evidence of a protein length change from an in-frame coding alteration or stop-loss event.
PM5	N/A	PM5 is not applicable because this variant is not a missense change, and same-residue missense comparator logic could not be applied.	pm5_candidates
PM6	Not assessed	No assumed de novo evidence without confirmed parentage was identified for this variant.
PP1	Not assessed	No segregation data were identified for this variant.
PP2	N/A	PP2 is not applicable because this variant is not a missense change.
PP3	Not assessed	Computational evidence does not support a damaging splice effect. SpliceAI shows a maximum delta score of 0.01, which is below typical splice-impact concern thresholds, and missense predictors such as REVEL and BayesDel are not applicable to this deletion.	spliceai
PP4	Not assessed	No phenotype-specific evidence was identified that is sufficiently specific to support PTCH1-related disease on its own for this variant.
PP5	Not assessed	PP5 was not applied because no independent reputable-source pathogenic classification without available supporting evidence was identified.	clinvar
BA1	Met	This variant exceeds the stand-alone benign frequency threshold of greater than 1%. The overall allele frequency is 1.31180% in gnomAD v4.1, with a highest observed subpopulation frequency of 2.30931% in the Middle Eastern population; it is also 1.26862% in gnomAD-Canada and 1.25285% in the highest-frequency gnomAD v2.1 subpopulation.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Met	Population frequency is well above the strong benign threshold of greater than 0.3%. The allele frequency is 1.31180% in gnomAD v4.1, 0.75389% in gnomAD v2.1, and 1.26862% in gnomAD-Canada.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	Although this variant is common in population databases, no dataset here directly establishes occurrence in clinically unaffected individuals under a disease-specific BS2 framework for PTCH1.	gnomad_v4
BS3	Not assessed	No well-established functional studies for this specific variant were identified that demonstrate no damaging effect.	oncokb
BS4	Not assessed	No evidence was identified showing lack of segregation with disease in affected family members.
BP1	N/A	BP1 is not applicable because this variant is not a missense change.
BP2	Not assessed	No phase or co-occurrence data were identified for this variant.
BP3	Not assessed	Available evidence does not establish that this deletion lies within a benign repetitive region lacking known function for ACMG BP3 use.
BP4	Not assessed	SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, but broader benign computational evidence for this 5′ UTR deletion is limited and missense predictors are not applicable.	spliceai
BP5	Not assessed	No alternate molecular cause was identified that would explain the phenotype independently of this variant.
BP6	Not assessed	BP6 was not applied because the available ClinVar assertions are from single submitters without an expert-panel benign assertion serving as a standalone reputable-source criterion here.	clinvar
BP7	N/A	BP7 is not applicable because this variant is neither synonymous nor intronic.	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.