Classification rationale

BA1BS1 Benign

PTCH1 c.-9_-4del

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.¹ 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%.² In silico splice prediction does not support a splice-disrupting effect, with SpliceAI showing a maximum delta score of 0.01.³

BA1 + BS1 → Benign

1 clinvar ↗

2 gnomad_v4 ↗gnomad_v2 ↗gnomad_canada ↗

3 spliceai ↗

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.

Gene diagram · NM_000264.5 · variants mapped to exon structure

PTCH1 NM_000264.5

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 19 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 2

Strength Supporting Moderate Strong Very strong

BA1 stand-alone Benign

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 v4.1 overall AF 0.013118Middle Eastern AF 0.0230931gnomAD-Canada overall AF 0.0126862

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

BS1 strong Benign

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 v4.1 AF 0.013118gnomAD v2.1 AF 0.00753893gnomAD-Canada AF 0.0126862

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

Assessed · not applied · 3 not met · 16 not assessed

Pathogenic

PVS1 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.

PS2 No confirmed de novo data were identified for this variant.

PS3 No well-established functional studies for this specific variant were identified that demonstrate a damaging effect.

PS4 Available evidence does not show enrichment of this variant in affected individuals, and its population frequency is high for a pathogenic PTCH1 germline allele.

PM2 This variant is not absent or rare in population databases.

PM3 No evidence was identified showing this variant in trans with a pathogenic variant in a recessive disease context.

PM6 No assumed de novo evidence without confirmed parentage was identified for this variant.

PP1 No segregation data were identified for this variant.

PP3 Computational evidence does not support a damaging splice effect.

PP4 No phenotype-specific evidence was identified that is sufficiently specific to support PTCH1-related disease on its own for this variant.

PP5 PP5 was not applied because no independent reputable-source pathogenic classification without available supporting evidence was identified.

Benign

BS2 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.

BS3 No well-established functional studies for this specific variant were identified that demonstrate no damaging effect.

BS4 No evidence was identified showing lack of segregation with disease in affected family members.

BP2 No phase or co-occurrence data were identified for this variant.

BP3 Available evidence does not establish that this deletion lies within a benign repetitive region lacking known function for ACMG BP3 use.

BP4 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.

BP5 No alternate molecular cause was identified that would explain the phenotype independently of this variant.

BP6 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.

N/A · 7 PS1 · PM1 · PM4 · PM5 · PP2 · BP1 · BP7

Research & evidence

Population frequency · supports benign

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 0.013118; MAF= 1.31180%, 15266/1163744 alleles, homozygotes = 127) and has highest observed frequency in the Middle Eastern population (AF= 0.0230931; MAF= 2.30931%, 66/2858 alleles, homozygotes = 2); grpmax FAF= 0.0186244.

v2.1

This variant is present in gnomAD v2.1 (AF= 0.00753893; MAF= 0.75389%, 214/28386 alleles, homozygotes = 1) and has highest observed frequency in the Remaining individuals population (AF= 0.0125285; MAF= 1.25285%, 11/878 alleles, homozygotes = 1); grpmax FAF= 0.0111152.

🇨🇦 CA

This variant is present in gnomAD-Canada v1.0 (AF= 0.0126862; MAF= 1.26862%, 230/18130 alleles, homozygotes = 0) and has highest observed frequency in the sas population (AF= 0.0155786; grpmax FAF95= 0.0104388).

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

1.3% · 15266 / 1,163,744
127 hom · FAF 1.9%

Middle Eastern 66 / 2,858	2.3% 2 hom
European (non-Finnish) 13739 / 944,962	1.5% 116 hom
Remaining individuals 530 / 40,882	1.3% 4 hom
South Asian 293 / 23,786	1.2% 4 hom
Ashkenazi Jewish 151 / 14,490	1% 1 hom
Admixed American 162 / 21,568	0.75%
African/African American 242 / 60,904	0.4%
European (Finnish) 79 / 27,564	0.29%
Amish 1 / 890	0.11%
East Asian 3 / 25,840	0.012%

gnomAD v2.1

0.75% · 214 / 28,386
1 hom · FAF 1.1%

Remaining individuals 11 / 878	1.3% 1 hom
European (non-Finnish) 153 / 14,990	1%
Admixed American 4 / 562	0.71%
African/African American 39 / 8,052	0.48%
Ashkenazi Jewish 1 / 258	0.39%
European (Finnish) 6 / 2,114	0.28%

+ 2 not observed (East Asian, South Asian)

gnomAD Canada 🇨🇦

1.3% · 230 / 18,130
0 hom · FAF 1%

⚠ LCR indel · split

Middle Eastern 7 / 140	5%
Remaining individuals 18 / 1,126	1.6%
South Asian 21 / 1,348	1.6%
European (non-Finnish) 173 / 11,524	1.5%
Latino/Admixed American 6 / 824	0.73%
Ashkenazi Jewish 4 / 822	0.49%
African/African American 1 / 1,012	0.099%

+ 2 not observed (East Asian, European (Finnish))

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Benign (7 clinical laboratories) and as Likely benign (4 clinical laboratories) and as benign (1 clinical laboratory). (ClinVarID = 193070)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).

SpliceAI ↗

Functional No data

No calibrated functional assay or RNA evidence was identified for this variant.

OncoKB ↗

COSMIC

Somatic evidence

COSMIC

This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant cancer hotspot.

COSMIC ↗

Sources & reference links

7Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Triaged references · 9 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

26467025 ↗ A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders. CLINVAR

15604628 ↗ Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors. CLINVAR

20301330 ↗ Nevoid Basal Cell Carcinoma Syndrome. CLINVAR

21304560 ↗ Clinical utility gene card for: Gorlin syndrome. CLINVAR

25394175 ↗ A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. CLINVAR

26389210 ↗ Genetics of Breast and Gynecologic Cancers (PDQ®): Health Professional Version. 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

Check your email

Reset your password

Enter an access code

Your allowance