rs765371196
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 3P and 6B. PM1PP2BP4_ModerateBS2
The NM_000264.5(PTCH1):c.2695A>G(p.Ile899Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,614,118 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict 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. I899M) 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.2695A>G | p.Ile899Val | missense_variant | 16/24 | ENST00000331920.11 | |
PTCH1 | NM_001083603.3 | c.2692A>G | p.Ile898Val | missense_variant | 16/24 | ENST00000437951.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PTCH1 | ENST00000331920.11 | c.2695A>G | p.Ile899Val | missense_variant | 16/24 | 5 | NM_000264.5 | A2 | |
PTCH1 | ENST00000437951.6 | c.2692A>G | p.Ile898Val | missense_variant | 16/24 | 5 | NM_001083603.3 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152236Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251388Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135886
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461882Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4AN XY: 727242
GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152236Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74390
ClinVar
Submissions by phenotype
Irido-corneo-trabecular dysgenesis Pathogenic:1
Likely pathogenic, flagged submission | clinical testing;research | Paul Sabatier University EA-4555, Paul Sabatier University | Jan 01, 2013 | rare variant, functional studies demonstrating is deleterious effect on protein. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | May 23, 2023 | In the published literature, this variant has been reported in at least one individual with Peters’ anomaly (PMIDs: 26893459 (2016) and 35170016 (2022)). In vivo functional studies indicated that this variant results in partial loss of PTCH1 function (PMID: 26893459 (2016)). The frequency of this variant in the general population, 0.000016 (4/251388 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is deleterious or benign. Based on the available information, we are unable to determine the clinical significance of this variant. - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 20, 2023 | The p.I899V variant (also known as c.2695A>G), located in coding exon 16 of the PTCH1 gene, results from an A to G substitution at nucleotide position 2695. The isoleucine at codon 899 is replaced by valine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Gorlin syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Dec 03, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at