rs1554698613

Positions:

• chr9-95477679-CATGGTTAGACAGGCATAGGCGAGCTGCAAGCAGAACA-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_000264.5(PTCH1):​c.1348-14_1370del variant causes a splice acceptor, coding sequence, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTCH1 NM_000264.5 splice_acceptor, coding_sequence, intron
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.36

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.0356814 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-95477679-CATGGTTAGACAGGCATAGGCGAGCTGCAAGCAGAACA-C is Pathogenic according to our data. Variant chr9-95477679-CATGGTTAGACAGGCATAGGCGAGCTGCAAGCAGAACA-C is described in ClinVar as [Pathogenic]. Clinvar id is 524578.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTCH1	NM_000264.5	c.1348-14_1370del		splice_acceptor_variant, coding_sequence_variant, intron_variant	10/24	ENST00000331920.11	NP_000255.2
PTCH1	NM_001083603.3	c.1345-14_1367del		splice_acceptor_variant, coding_sequence_variant, intron_variant	10/24	ENST00000437951.6	NP_001077072.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTCH1	ENST00000331920.11	c.1348-14_1370del		splice_acceptor_variant, coding_sequence_variant, intron_variant	10/24	5	NM_000264.5	ENSP00000332353	A2
PTCH1	ENST00000437951.6	c.1345-14_1367del		splice_acceptor_variant, coding_sequence_variant, intron_variant	10/24	5	NM_001083603.3	ENSP00000389744

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Gorlin syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 24, 2017

For these reasons, this variant has been classified as Pathogenic. This variant is not present in population databases (ExAC no frequency). This variant is a gross deletion of the genomic region encompassing part of exon 10 of the PTCH1 gene, including the intron 9-exon 10 boundary (c.1348-14-1370del). This likely creates a premature translational stop signal and is expected to result in an absent or disrupted protein product. While this particular variant has not been reported in the literature, loss-of-function variants in PTCH1 are known to be pathogenic (PMID: 16301862, 16419085). -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1554698613; hg19: chr9-98239961;