chr9-95453551-C-T
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 3P and 6B. PM1PP2BP4BP6BS2
The NM_000264.5(PTCH1):c.3376G>A(p.Val1126Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00016 in 1,614,120 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1126F) has been classified as Uncertain significance.
Frequency
Consequence
NM_000264.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_benign. Variant got -3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PTCH1 | NM_000264.5 | c.3376G>A | p.Val1126Ile | missense_variant | 20/24 | ENST00000331920.11 | |
PTCH1 | NM_001083603.3 | c.3373G>A | p.Val1125Ile | missense_variant | 20/24 | ENST00000437951.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PTCH1 | ENST00000331920.11 | c.3376G>A | p.Val1126Ile | missense_variant | 20/24 | 5 | NM_000264.5 | A2 | |
PTCH1 | ENST00000437951.6 | c.3373G>A | p.Val1125Ile | missense_variant | 20/24 | 5 | NM_001083603.3 |
Frequencies
GnomAD3 genomes AF: 0.000118 AC: 18AN: 152216Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000314 AC: 79AN: 251250Hom.: 1 AF XY: 0.000339 AC XY: 46AN XY: 135828
GnomAD4 exome AF: 0.000165 AC: 241AN: 1461786Hom.: 0 Cov.: 31 AF XY: 0.000173 AC XY: 126AN XY: 727200
GnomAD4 genome AF: 0.000118 AC: 18AN: 152334Hom.: 0 Cov.: 33 AF XY: 0.0000940 AC XY: 7AN XY: 74476
ClinVar
Submissions by phenotype
not provided Uncertain:1Benign:3
Likely benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Sep 02, 2022 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Mar 22, 2019 | See Variant Classification Assertion Criteria. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2018 | - - |
Hereditary cancer-predisposing syndrome Uncertain:1Benign:1
Uncertain significance, criteria provided, single submitter | curation | Sema4, Sema4 | Apr 07, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | May 08, 2020 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
not specified Benign:1Other:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 11, 2021 | Variant summary: PTCH1 c.3376G>A (p.Val1126Ile) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00031 in 251250 control chromosomes, predominantly at a frequency of 0.00049 within the Non-Finnish European subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 29 fold of the estimated maximal expected allele frequency for a pathogenic variant in PTCH1 causing Nevoid Basal Cell Carcinoma Syndrome (Gorlin Syndrome) phenotype (1.7e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.3376G>A has been reported in the literature in individuals affected Pancreatic ductal adenocarcinoma or Ovarian cancer (example, Lovecek_2019 and Li_2019). Co-occurrences with other pathogenic variant have been reported in at least one individual, providing supporting evidence for a benign role for this variant (Li_PTC1_PNAS_2019). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and have classified the variant as likely benign. Based on the evidence outlined above, the variant was classified as likely benign. - |
not provided, no classification provided | reference population | ITMI | Sep 19, 2013 | - - |
PTCH1-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 10, 2022 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Gorlin syndrome Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Jan 16, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at