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 ↗

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

PTCH1 NM_000264.5

Fetching transcript structure from UCSC…

Applied criteria · 2 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= 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