rs2236405
Variant summary
Our verdict is Benign. Variant got -17 ACMG points: 3P and 20B. PM1PP2BP4_StrongBP6_Very_StrongBA1
The NM_000264.5(PTCH1):c.3583A>T(p.Thr1195Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0223 in 1,557,458 control chromosomes in the GnomAD database, including 1,174 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1195I) has been classified as Uncertain significance.
Frequency
Consequence
NM_000264.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -17 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PTCH1 | NM_000264.5 | c.3583A>T | p.Thr1195Ser | missense_variant | 22/24 | ENST00000331920.11 | |
PTCH1 | NM_001083603.3 | c.3580A>T | p.Thr1194Ser | missense_variant | 22/24 | ENST00000437951.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PTCH1 | ENST00000331920.11 | c.3583A>T | p.Thr1195Ser | missense_variant | 22/24 | 5 | NM_000264.5 | A2 | |
PTCH1 | ENST00000437951.6 | c.3580A>T | p.Thr1194Ser | missense_variant | 22/24 | 5 | NM_001083603.3 |
Frequencies
GnomAD3 genomes AF: 0.0469 AC: 7130AN: 152148Hom.: 347 Cov.: 33
GnomAD3 exomes AF: 0.0340 AC: 5516AN: 162192Hom.: 228 AF XY: 0.0339 AC XY: 2919AN XY: 85986
GnomAD4 exome AF: 0.0197 AC: 27632AN: 1405192Hom.: 826 Cov.: 31 AF XY: 0.0202 AC XY: 14008AN XY: 693950
GnomAD4 genome AF: 0.0469 AC: 7148AN: 152266Hom.: 348 Cov.: 33 AF XY: 0.0478 AC XY: 3558AN XY: 74478
ClinVar
Submissions by phenotype
not specified Benign:4Other:1
not provided, no classification provided | reference population | ITMI | Sep 19, 2013 | - - |
Benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Benign, no assertion criteria provided | clinical testing | Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | - | - - |
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 02, 2016 | - - |
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Mar 13, 2015 | - - |
not provided Benign:4
Likely benign, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Jul 22, 2016 | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Aug 27, 2013 | The variant is found in PTCH panel(s). - |
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Sep 22, 2023 | - - |
Benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | May 24, 2016 | Variant summary: The PTCH1 c.3583A>T (p.Thr1195Ser) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 1271/23496 control chromosomes (51 homozygotes) at a frequency of 0.0540943, which is approximately 3157 times the estimated maximal expected allele frequency of a pathogenic PTCH1 variant (0.0000171), suggesting this variant is likely a benign polymorphism. This variant has been reported in NBCCS patients. One patient also carried a potentially pathogenic variant c.3499G>A (p.G1167R), further supporting the benign classification. In addition, multiple clinical diagnostic laboratories classified this variant as benign. Taken together, this variant is classified as benign. - |
Gorlin syndrome Benign:3
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Benign, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Jul 07, 2023 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Hereditary cancer-predisposing syndrome Benign:2
Benign, criteria provided, single submitter | curation | Sema4, Sema4 | Dec 09, 2019 | - - |
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 03, 2014 | This alteration is classified as 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. - |
Holoprosencephaly 7 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at