9-95447112-G-A
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2
The NM_000264.5(PTCH1):c.4144C>T(p.His1382Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000263 in 152,224 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H1382P) has been classified as Uncertain significance.
Frequency
Consequence
NM_000264.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 3 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PTCH1 | NM_000264.5 | c.4144C>T | p.His1382Tyr | missense_variant | 23/24 | ENST00000331920.11 | |
PTCH1 | NM_001083603.3 | c.4141C>T | p.His1381Tyr | missense_variant | 23/24 | ENST00000437951.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PTCH1 | ENST00000331920.11 | c.4144C>T | p.His1382Tyr | missense_variant | 23/24 | 5 | NM_000264.5 | A2 | |
PTCH1 | ENST00000437951.6 | c.4141C>T | p.His1381Tyr | missense_variant | 23/24 | 5 | NM_001083603.3 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152224Hom.: 0 Cov.: 32
GnomAD4 exome Cov.: 30
GnomAD4 genome AF: 0.0000263 AC: 4AN: 152224Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74360
ClinVar
Submissions by phenotype
Gorlin syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 28, 2024 | This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 1382 of the PTCH1 protein (p.His1382Tyr). This variant is present in population databases (rs377484697, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with PTCH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 409219). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PTCH1 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 14, 2023 | The p.H1382Y variant (also known as c.4144C>T), located in coding exon 23 of the PTCH1 gene, results from a C to T substitution at nucleotide position 4144. The histidine at codon 1382 is replaced by tyrosine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at