chr9-95458029-C-T
Position:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000264.5(PTCH1):c.3152G>A(p.Trp1051Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Consequence
PTCH1
NM_000264.5 stop_gained
NM_000264.5 stop_gained
Scores
5
1
1
Clinical Significance
Conservation
PhyloP100: 7.48
Genes affected
PTCH1 (HGNC:9585): (patched 1) This gene encodes a member of the patched family of proteins and a component of the hedgehog signaling pathway. Hedgehog signaling is important in embryonic development and tumorigenesis. The encoded protein is the receptor for the secreted hedgehog ligands, which include sonic hedgehog, indian hedgehog and desert hedgehog. Following binding by one of the hedgehog ligands, the encoded protein is trafficked away from the primary cilium, relieving inhibition of the G-protein-coupled receptor smoothened, which results in activation of downstream signaling. Mutations of this gene have been associated with basal cell nevus syndrome and holoprosencephaly. [provided by RefSeq, Aug 2017]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 9-95458029-C-T is Pathogenic according to our data. Variant chr9-95458029-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 409220.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PTCH1 | NM_000264.5 | c.3152G>A | p.Trp1051Ter | stop_gained | 18/24 | ENST00000331920.11 | |
PTCH1 | NM_001083603.3 | c.3149G>A | p.Trp1050Ter | stop_gained | 18/24 | ENST00000437951.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PTCH1 | ENST00000331920.11 | c.3152G>A | p.Trp1051Ter | stop_gained | 18/24 | 5 | NM_000264.5 | A2 | |
PTCH1 | ENST00000437951.6 | c.3149G>A | p.Trp1050Ter | stop_gained | 18/24 | 5 | NM_001083603.3 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
PTCH1-related disorder Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 01, 2023 | The PTCH1 c.3152G>A variant is predicted to result in premature protein termination (p.Trp1051*). This variant was reported to be causative for Gorlin syndrome (Sánchez-Vicente et al. 2016. PubMed ID: 27595027; Huq et al. 2017. PubMed ID: 28328109). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is classified as pathogenic in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/409220/). Nonsense variants in PTCH1 are expected to be pathogenic. This variant is interpreted as pathogenic. - |
Gorlin syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 08, 2021 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 409220). This premature translational stop signal has been observed in individuals with clinical features of basal cell nevus syndrome (Invitae). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Trp1051*) in the PTCH1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PTCH1 are known to be pathogenic (PMID: 16301862, 16419085). - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | May 31, 2016 | The p.W1051* pathogenic mutation (also known as c.3152G>A), located in coding exon 18 of the PTCH1 gene, results from a G to A substitution at nucleotide position 3152. This changes the amino acid from a tryptophan to a stop codon at position 1051. Since premature stop codons are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
A;A;A;A;A;A;A
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at