PTCH1 c.-6_-4dup, p.?
NM_000264.5:c.-6_-4dup
COSMIC ID: COSN31768885
Variant of Uncertain Significance (VUS)
This variant is classified as Benign based on stand-alone BA1 (MAF 23%), supported by BS1 and BS2 (high population frequency, presence in healthy homozygotes), and computational evidence of no impact (BP4).
ACMG/AMP Criteria Applied
BA1
BS1
BS2
BP4
Genetic Information
Gene & Transcript Details
Gene
PTCH1
Transcript
NM_000264.5
MANE Select
Total Exons
24
Strand
Reverse (−)
Reference Sequence
NC_000009.11
Alternative Transcripts
| ID | Status | Details |
|---|---|---|
| NM_000264.4 | RefSeq Select | 24 exons | Reverse |
| NM_000264.2 | Alternative | 24 exons | Reverse |
| NM_000264.3 | Alternative | 24 exons | Reverse |
Variant Details
HGVS Notation
NM_000264.5:c.-6_-4dup
Protein Change
?
Location
Exon 1
(Exon 1 of 24)
5'Exon Structure (24 total)3'
Functional Consequence
Loss of Function
Related Variants
Alternate Identifiers
COSN31768885
Variant interpretation based on transcript NM_000264.5
Genome Browser
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HGVS InputNM_000264:c.-6_-4dup
Active Tracks
ConservationRefSeqClinVargnomAD
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Clinical Data
Global Frequency
23.0%
Common
Highest in Population
African/African American
27.9%
Common
Global: 23.0%
African/African American: 27.9%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 28386Alt: 6523Homozygotes: 791
ACMG Criteria Applied
BA1
This variant is present in gnomAD (MAF= 23.0%, 6523/28386 alleles, homozygotes = 791) and at a higher frequency in the African/African American population (MAF= 27.9%, 2247/8052 alleles, homozygotes = 304). The variant is common (MAF > 1%), supporting BA1 criterion application.
Classification
Unknown
Publications (0)
No publication details.
Clinical Statement
Functional Impact
Functional Domain
Hotspot Status
Not a hotspot
Domain Summary
This variant is not located in a mutational hotspot or critical domain (0 mutations).
Related Variants in This Domain
Computational Analysis
Pathogenicity Predictions
Predictor Consensus
Unknown
PP3 Applied
No
VCEP Guidelines
Applied ACMG/AMP Criteria (VCEP Specific)
PVS1
PVS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PVS1 is: "Null variant in a gene where LoF is a known mechanism of disease." The evidence for this variant shows: it is a 5′UTR duplication (c.-6_-4dupGGC), not a predicted null variant. Therefore, this criterion is not applied because the variant does not generate a null effect.
PS1
PS1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS1 is: "Same amino acid change as a previously established pathogenic variant regardless of nucleotide change." The evidence for this variant shows: no amino acid change is produced (noncoding UTR variant). Therefore, this criterion is not applied because there is no amino acid change.
PS2
PS2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS2 is: "De novo (both maternity and paternity confirmed) in a patient with the disease and no family history." The evidence for this variant shows: no de novo or family data available. Therefore, this criterion is not applied due to lack of de novo confirmation.
PS3
PS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS3 is: "Well-established functional studies supportive of a damaging effect on the gene or gene product." The evidence for this variant shows: no functional studies have been performed (variant not characterized). Therefore, this criterion is not applied because functional data are absent.
PS4
PS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PS4 is: "Prevalence of the variant in affected individuals is significantly increased compared with controls." The evidence for this variant shows: no case–control or affected individual data reported. Therefore, this criterion is not applied due to absence of case data.
PM1
PM1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM1 is: "Located in a mutational hot spot and/or well-established functional domain without benign variation." The evidence for this variant shows: no hotspot or functional domain annotation for a 5′UTR duplication. Therefore, this criterion is not applied.
PM2
PM2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM2 is: "Absent from controls (or at extremely low frequency if recessive)." The evidence for this variant shows: gnomAD MAF = 23.0%, common in controls. Therefore, this criterion is not applied because the variant is not rare.
PM3
PM3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM3 is: "Detected in trans with a pathogenic variant for recessive disorders." The evidence for this variant shows: no trans or phasing data available. Therefore, this criterion is not applied.
PM4
PM4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM4 is: "Protein length changes due to in-frame deletions/insertions or stop-loss variants." The evidence for this variant shows: it is a noncoding UTR duplication, not affecting protein length. Therefore, this criterion is not applied.
PM5
PM5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM5 is: "Novel missense change at an amino acid residue where a different pathogenic missense change has been seen." The evidence for this variant shows: no missense change, noncoding. Therefore, this criterion is not applied.
PM6
PM6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PM6 is: "Assumed de novo, but without confirmation of paternity and maternity." The evidence for this variant shows: no de novo data. Therefore, this criterion is not applied.
PP1
PP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP1 is: "Co-segregation with disease in multiple affected family members." The evidence for this variant shows: no family segregation data. Therefore, this criterion is not applied.
PP2
PP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP2 is: "Missense variant in a gene with a low rate of benign missense variation and where missense variants are a common mechanism of disease." The evidence for this variant shows: it is noncoding, not missense. Therefore, this criterion is not applied.
PP3
PP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP3 is: "Multiple lines of computational evidence support a deleterious effect on the gene or gene product." The evidence for this variant shows: in silico tools (SpliceAI score 0.01) predict no impact. Therefore, this criterion is not applied because computational evidence does not support deleterious effect.
PP4
PP4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP4 is: "Patient’s phenotype or family history highly specific for a disease with a single genetic etiology." The evidence for this variant shows: no clinical phenotype or family history provided. Therefore, this criterion is not applied.
PP5
PP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for PP5 is: "Reputable source reports variant as pathogenic, but without accessible evidence." The evidence for this variant shows: not reported in ClinVar or other databases. Therefore, this criterion is not applied.
BA1
BA1 (Stand Alone) Strength Modified
According to standard ACMG guidelines, the rule for BA1 is: "Allele frequency is too high for the disorder (based on population data)." The evidence for this variant shows: gnomAD MAF = 23.0%, well above 5%. Therefore, this criterion is applied at Stand Alone strength because the allele frequency exceeds the BA1 threshold.
BS1
BS1 (Strong)
According to standard ACMG guidelines, the rule for BS1 is: "Allele frequency is greater than expected for the disorder." The evidence for this variant shows: gnomAD MAF = 23.0%, far exceeding expected frequency for a rare dominant condition. Therefore, this criterion is applied at Strong strength.
BS2
BS2 (Strong)
According to standard ACMG guidelines, the rule for BS2 is: "Observed in a healthy adult individual for a dominant disorder with full penetrance expected at an early age." The evidence for this variant shows: 791 homozygotes in gnomAD, indicating presence in healthy individuals. Therefore, this criterion is applied at Strong strength.
BS3
BS3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS3 is: "Well-established functional studies show no damaging effect on protein function or splicing." The evidence for this variant shows: no functional studies available. Therefore, this criterion is not applied.
BS4
BS4 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BS4 is: "Lack of segregation in affected family members." The evidence for this variant shows: no segregation data. Therefore, this criterion is not applied.
BP1
BP1 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP1 is: "Missense variant in a gene where only LoF causes disease." The evidence for this variant shows: noncoding UTR duplication. Therefore, this criterion is not applied.
BP2
BP2 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP2 is: "Observed in trans with a pathogenic variant for dominant disorders or in cis with a pathogenic variant." The evidence for this variant shows: no phasing data. Therefore, this criterion is not applied.
BP3
BP3 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP3 is: "In-frame deletions/insertions in a repetitive region without known function." The evidence for this variant shows: noncoding UTR duplication not in a defined repetitive region. Therefore, this criterion is not applied.
BP4
BP4 (Supporting)
According to standard ACMG guidelines, the rule for BP4 is: "Multiple lines of computational evidence suggest no impact on gene or gene product." The evidence for this variant shows: SpliceAI max score 0.01 and other in silico tools predict no impact. Therefore, this criterion is applied at Supporting strength.
BP5
BP5 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP5 is: "Variant found in a case with an alternate molecular basis for disease." The evidence for this variant shows: no case reports with alternate molecular findings. Therefore, this criterion is not applied.
BP6
BP6 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP6 is: "Reputable source reports variant as benign, but without accessible evidence." The evidence for this variant shows: no such reports. Therefore, this criterion is not applied.
BP7
BP7 (Not Applied) Strength Modified
According to standard ACMG guidelines, the rule for BP7 is: "Synonymous variant with no predicted impact on splicing." The evidence for this variant shows: it is a noncoding duplication, not synonymous. Therefore, this criterion is not applied.