About PTCH1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
PTCH1 c.-9_-4del, p.?
Classification
Benign
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is benign. Select a step to read what it means.
Benign.A benign classification under the recorded framework.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
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.
01The reasoning
How it was classified
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 0
Benign evidence criteria: 2
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 2
BA1Stand alone
BA1 · stand alone
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.
BS1Strong
BS1 · strong
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.
Recorded classification: Benign
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: BA1 stand-alone benign, BS1 strong benign; combination = 1 stand-alone benign, which maps to Benign.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
15,266 / 1,163,744 alleles
gnomAD v4.1: 15,266 / 1,163,744 alleles. Recorded AF 0.013118. Recorded homozygote count 127.
gnomAD 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.
gnomAD-Canada
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).
SpliceAI score
0.010 maximum delta
Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
12 reported laboratory submissions
7 Benign · 4 Likely benign · 1 benign.
Context only
ClinVar ↗
No screenshot for this evidence
Functional evidence
Not recorded
No standalone functional evidence summary is recorded in evidence_summary.functional.
No listed criterion applied
OncoKB ↗
Somatic evidence
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
Context only
COSMIC ↗
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
28 criteria with recorded statuses: 2 met · 3 not met · 16 not assessed · 7 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
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.
No criteria match.
Met · 2
BA1 Stand aloneThis 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. Details ▾Hide ▴
Rule
Non-VCEP benign stand-alone threshold: BA1 > 1%; observed frequencies are above threshold.
Evidence considered
- gnomAD v4.1 overall AF 0.013118
- Middle Eastern AF 0.0230931
- gnomAD-Canada overall AF 0.0126862
- gnomAD v2.1 highest subpopulation AF 0.0125285
Sources
BS1 StrongPopulation 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. Details ▾Hide ▴
Rule
Non-VCEP strong benign frequency threshold: BS1 > 0.3%; observed frequencies are above threshold.
Evidence considered
- gnomAD v4.1 AF 0.013118
- gnomAD v2.1 AF 0.00753893
- gnomAD-Canada AF 0.0126862
Sources
Not met · 3 · evaluated, threshold not reached
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. Details ▾Hide ▴
Rule
Generic PVS1 fallback requires an eligible loss-of-function mechanism and a qualifying null-variant class; this variant does not meet the variant-class requirement.
Evidence considered
- PTCH1 is eligible for generic PVS1 consideration at the gene level
- Variant-specific scaffold classifies this 5′ UTR deletion outside default PVS1 null-variant buckets
Sources
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. Details ▾Hide ▴
Rule
PS4 requires increased prevalence in affected individuals compared with controls; that evidence was not identified.
Evidence considered
- ClinVar reports benign/likely benign submissions
- Population frequencies are well above rare-variant expectations
Still missing
- Case-control enrichment or multiple well-documented affected probands beyond background population frequency
Sources
PM2 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%. Details ▾Hide ▴
Rule
Non-VCEP rarity threshold for PM2: AF < 0.1%; observed frequencies are above threshold.
Evidence considered
- gnomAD v4.1 AF 0.013118
- gnomAD v2.1 AF 0.00753893
- gnomAD-Canada AF 0.0126862
Sources
Not assessed · 16 · no assessment recorded
PS2 No confirmed de novo data were identified for this variant. Details ▾Hide ▴
Still missing
- Documented parental testing or confirmed de novo occurrence
PS3 No well-established functional studies for this specific variant were identified that demonstrate a damaging effect. Details ▾Hide ▴
Evidence considered
- No variant-specific functional evidence retrieved
Still missing
- Validated functional data specific to NM_000264.5:c.-9_-4del
Sources
PM3 No evidence was identified showing this variant in trans with a pathogenic variant in a recessive disease context. Details ▾Hide ▴
Still missing
- Confirmed phase data and relevant recessive disease context
PM6 No assumed de novo evidence without confirmed parentage was identified for this variant. Details ▾Hide ▴
Still missing
- Documented presumed de novo occurrence
PP1 No segregation data were identified for this variant. Details ▾Hide ▴
Still missing
- Family segregation data
PP3 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. Details ▾Hide ▴
Rule
PP3 requires multiple computational lines supporting a deleterious effect; that support was not identified.
Evidence considered
- SpliceAI max delta score 0.01
- REVEL not applicable for this non-SNV deletion
- BayesDel not applicable for this non-SNV deletion
Still missing
- Additional validated noncoding impact predictors or RNA data if clinical concern remains
Sources
PP4 No phenotype-specific evidence was identified that is sufficiently specific to support PTCH1-related disease on its own for this variant. Details ▾Hide ▴
Still missing
- Detailed phenotype information with high specificity for PTCH1-related disease
PP5 PP5 was not applied because no independent reputable-source pathogenic classification without available supporting evidence was identified. Details ▾Hide ▴
Rule
PP5 not used without appropriate pathogenic reputable-source evidence.
Evidence considered
- ClinVar submissions are benign/likely benign rather than pathogenic
Sources
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. Details ▾Hide ▴
Rule
BS2 requires observation in healthy individuals in a context appropriate for the gene and disorder.
Evidence considered
- gnomAD v4.1 includes 127 homozygotes
Still missing
- Disease-specific healthy adult observation framework with penetrance context
Sources
BS3 No well-established functional studies for this specific variant were identified that demonstrate no damaging effect. Details ▾Hide ▴
Evidence considered
- No variant-specific benign functional evidence retrieved
Still missing
- Validated functional data specific to NM_000264.5:c.-9_-4del
Sources
BS4 No evidence was identified showing lack of segregation with disease in affected family members. Details ▾Hide ▴
Still missing
- Informative family segregation data demonstrating non-segregation
BP2 No phase or co-occurrence data were identified for this variant. Details ▾Hide ▴
Still missing
- Confirmed phase or co-occurrence data
BP3 Available evidence does not establish that this deletion lies within a benign repetitive region lacking known function for ACMG BP3 use. Details ▾Hide ▴
Still missing
- Validated benign repeat-region context specific to this locus
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. Details ▾Hide ▴
Rule
BP4 requires computational evidence supporting no impact; current support is limited to low splice impact prediction.
Evidence considered
- SpliceAI max delta score 0.01
Still missing
- Additional validated noncoding benign computational evidence if BP4 is to be considered
Sources
BP5 No alternate molecular cause was identified that would explain the phenotype independently of this variant. Details ▾Hide ▴
Still missing
- Documented alternate pathogenic finding explaining the phenotype
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. Details ▾Hide ▴
Rule
BP6 not used here as a standalone criterion from the available assertions.
Evidence considered
- ClinVar overall classification benign with single-submitter review statuses
Still missing
- Expert-panel or otherwise qualifying reputable-source benign assertion if BP6 were to be considered
Sources
Not applicable · 7· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 is not applicable because this variant is not a protein-coding substitution with an established same-amino-acid pathogenic comparator. Details ▾Hide ▴
Rule
PS1 applies to amino-acid substitutions only.
Evidence considered
- Protein consequence is unresolved for this 5′ UTR deletion
PM1 N/APM1 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. Details ▾Hide ▴
Rule
PM1 is primarily used for missense or coding-region hotspot/domain variants.
PM4 N/APM4 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. Details ▾Hide ▴
Rule
PM4 applies to protein length changes from in-frame indels or stop-loss variants.
PM5 N/APM5 is not applicable because this variant is not a missense change, and same-residue missense comparator logic could not be applied. Details ▾Hide ▴
Rule
PM5 applies to novel missense changes at a residue with another pathogenic missense change.
Evidence considered
- PM5 candidate review found classic same-residue logic not applicable
Sources
pm5_candidates
PP2 N/APP2 is not applicable because this variant is not a missense change. Details ▾Hide ▴
Rule
PP2 applies to missense variants only.
BP1 N/ABP1 is not applicable because this variant is not a missense change. Details ▾Hide ▴
Rule
BP1 applies to missense variants only.
BP7 N/ABP7 is not applicable because this variant is neither synonymous nor intronic. Details ▾Hide ▴
Rule
BP7 applies to synonymous or certain intronic variants only.
Evidence considered
- Variant is a 5′ UTR deletion
- SpliceAI does not show significant splice impact
Sources
Identifiers
- Gene
- PTCH1
- Transcript
- NM_000264.5
- Coding (HGVS c.)
- NM_000264.5:c.-9_-4del
- Protein (HGVS p.)
- NP_000255.2:p.?
- GRCh38
- chr9:95508364 TGCCGCC>T
- GRCh37
- chr9:98270646 TGCCGCC>T
- ClinVar
- 193070
Gene diagram
Every interpreted variant in PTCH1, mapped onto the exon structure of NM_000264.5. Select a row to find it on the plot.
PTCH1NM_000264.5
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in PTCH1
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
15,266 / 1,163,744 alleles
AF 0.0131 · 127 homozygotes · FAF 0.0186
gnomAD v2.1
214 / 28,386 alleles
AF 0.00754 · 1 homozygotes · FAF 0.0111
gnomAD-Canada v1.0
230 / 18,130 alleles
AF 0.0127 · 0 homozygotes · FAF 0.0104
By genetic ancestry
gnomAD v4.1
AF 0.013 · 15266 / 1,163,744 alleles · 127 hom · FAF 0.019
| Middle Eastern66 / 2,858 | 0.0232 hom |
| European (non-Finnish)13739 / 944,962 | 0.015116 hom |
| Remaining individuals530 / 40,882 | 0.0134 hom |
| South Asian293 / 23,786 | 0.0124 hom |
| Ashkenazi Jewish151 / 14,490 | 0.011 hom |
| Admixed American162 / 21,568 | 0.0075 |
| African/African American242 / 60,904 | 0.004 |
| European (Finnish)79 / 27,564 | 0.0029 |
| Amish1 / 890 | 0.0011 |
| East Asian3 / 25,840 | 0.00012 |
gnomAD v2.1
AF 0.0075 · 214 / 28,386 alleles · 1 hom · FAF 0.011
| Remaining individuals11 / 878 | 0.0131 hom |
| European (non-Finnish)153 / 14,990 | 0.01 |
| Admixed American4 / 562 | 0.0071 |
| African/African American39 / 8,052 | 0.0048 |
| Ashkenazi Jewish1 / 258 | 0.0039 |
| European (Finnish)6 / 2,114 | 0.0028 |
0 alternate alleles recorded in 2 other groups: East Asian, South Asian.
gnomAD-Canada
AF 0.013 · 230 / 18,130 alleles · 0 hom · FAF 0.01
| mid7 / 140 | 0.05 |
| oth18 / 1,126 | 0.016 |
| sas21 / 1,348 | 0.016 |
| nfe173 / 11,524 | 0.015 |
| amr6 / 824 | 0.0073 |
| asj4 / 822 | 0.0049 |
| afr1 / 1,012 | 0.00099 |
0 alternate alleles recorded in 2 other groups: eas, fin.
Statements
gnomAD 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.
gnomAD 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.
gnomAD-Canada
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).
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 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. Details ▾Hide ▴
Rule
PP3 requires multiple computational lines supporting a deleterious effect; that support was not identified.
Evidence considered
- SpliceAI max delta score 0.01
- REVEL not applicable for this non-SNV deletion
- BayesDel not applicable for this non-SNV deletion
Still missing
- Additional validated noncoding impact predictors or RNA data if clinical concern remains
Sources
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. Details ▾Hide ▴
Rule
BP4 requires computational evidence supporting no impact; current support is limited to low splice impact prediction.
Evidence considered
- SpliceAI max delta score 0.01
Still missing
- Additional validated noncoding benign computational evidence if BP4 is to be considered
Sources
BP7 N/ABP7 is not applicable because this variant is neither synonymous nor intronic. Details ▾Hide ▴
Rule
BP7 applies to synonymous or certain intronic variants only.
Evidence considered
- Variant is a 5′ UTR deletion
- SpliceAI does not show significant splice impact
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
9 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
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PMID 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.Richards S et al. · 2015No paper-specific finding is recorded.
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PMID 26467025 ↗A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.Karbassi I et al. · 2016No paper-specific finding is recorded.
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PMID 15604628 ↗Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors.Trepanier A et al. · 2004No paper-specific finding is recorded.
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PMID 20301330 ↗Nevoid Basal Cell Carcinoma Syndrome.Adam MP et al. · 1993No paper-specific finding is recorded.
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PMID 21304560 ↗Clinical utility gene card for: Gorlin syndrome.Lo Muzio L et al. · 2011No paper-specific finding is recorded.
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PMID 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.Hampel H et al. · 2015No paper-specific finding is recorded.
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PMID 26389210 ↗Genetics of Breast and Gynecologic Cancers (PDQ®): Health Professional Version.PDQ Cancer Genetics Editorial Board · 2002No paper-specific finding is recorded.
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PMID 26389258 ↗Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional Version.PDQ Cancer Genetics Editorial Board · 2002No paper-specific finding is recorded.
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PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.Nykamp K et al. · 2017No paper-specific finding is recorded.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
15,266 / 1,163,744 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.010
Open source ↗
ClinVar
7 Benign · 4 Likely benign · 1 benign
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/193070/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/9-98270646-TGCCGCC-T?dataset=…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr9-95508364-TGCCGCC-T?datas…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/9-95508364-TGCCGCC-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000264.5%3Ac.-9_-…
- OncoKB ↗www.oncokb.org/gene/PTCH1/?
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=PTCH1+c.-9_-4del
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD 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.
gnomAD 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.
gnomAD-Canada
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).
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)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
Somatic
This variant has not previously been reported in somatic cancers (COSMIC).