9-95469814-T-C
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PP2PP3_StrongPP5
The NM_000264.5(PTCH1):c.1846A>G(p.Ser616Gly) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predicting alterations to normal splicing. 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. S616N) has been classified as Uncertain significance.
Frequency
Consequence
NM_000264.5 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PTCH1 | NM_000264.5 | c.1846A>G | p.Ser616Gly | missense_variant, splice_region_variant | 13/24 | ENST00000331920.11 | |
PTCH1 | NM_001083603.3 | c.1843A>G | p.Ser615Gly | missense_variant, splice_region_variant | 13/24 | ENST00000437951.6 | |
LOC100507346 | NR_038982.1 | n.1752T>C | non_coding_transcript_exon_variant | 4/4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PTCH1 | ENST00000331920.11 | c.1846A>G | p.Ser616Gly | missense_variant, splice_region_variant | 13/24 | 5 | NM_000264.5 | A2 | |
PTCH1 | ENST00000437951.6 | c.1843A>G | p.Ser615Gly | missense_variant, splice_region_variant | 13/24 | 5 | NM_001083603.3 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Mar 06, 2024 | The p.S616G pathogenic mutation (also known as c.1846A>G), located in coding exon 13 of the PTCH1 gene, results from an A to G substitution at nucleotide position 1846. The serine at codon 616 is replaced by glycine, an amino acid with similar properties. This variant has been observed in multiple individuals with a personal and/or family history that is consistent with nevoid basal cell carcinoma syndrome (Ambry internal data). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Gorlin syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 27, 2022 | 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 428836). This variant has not been reported in the literature in individuals affected with PTCH1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with glycine, which is neutral and non-polar, at codon 616 of the PTCH1 protein (p.Ser616Gly). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at