ENST00000551630.1:c.-254A>C
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The ENST00000551630.1(PTCH1):c.-254A>C variant causes a 5 prime UTR 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 Likely pathogenic (★★).
Frequency
Consequence
ENST00000551630.1 5_prime_UTR
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PTCH1 | NM_000264.5 | c.202-2A>C | splice_acceptor_variant, intron_variant | Intron 1 of 23 | ENST00000331920.11 | NP_000255.2 | ||
PTCH1 | NM_001083603.3 | c.199-2A>C | splice_acceptor_variant, intron_variant | Intron 1 of 23 | ENST00000437951.6 | NP_001077072.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PTCH1 | ENST00000331920.11 | c.202-2A>C | splice_acceptor_variant, intron_variant | Intron 1 of 23 | 5 | NM_000264.5 | ENSP00000332353.6 | |||
PTCH1 | ENST00000437951.6 | c.199-2A>C | splice_acceptor_variant, intron_variant | Intron 1 of 23 | 5 | NM_001083603.3 | ENSP00000389744.2 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD4 exome Cov.: 31
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Gorlin syndrome Pathogenic:1
For these reasons, this variant has been classified as Pathogenic. Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in PTCH1 are known to be pathogenic (PMID: 16301862, 16419085). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. Disruption of this splice site has been observed in individual(s) with clinical features of basal cell nevus syndrome (PMID: 29575684, Invitae). ClinVar contains an entry for this variant (Variation ID: 428844). This variant is not present in population databases (ExAC no frequency). This sequence change affects an acceptor splice site in intron 1 of the PTCH1 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. -
not provided Pathogenic:1
This variant is located in a canonical splice-acceptor site and is predicted to interfere with normal PTCH1 mRNA splicing. To the best of our knowledge, the variant has not been reported in the published literature. Also, this variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as likely pathogenic. -
Hereditary cancer-predisposing syndrome Pathogenic:1
The c.202-2A>C intronic pathogenic mutation results from an A to C substitution two nucleotides upstream from coding exon 2 in the PTCH1 gene. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified as a disease-causing mutation. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at