rs863225467

chr9-95467133-AAGTA-ACT

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_000264.5(PTCH1):c.2539_2542delinsAG(p.Tyr847SerfsTer13) variant causes a frameshift change. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Y847Y) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTCH1 NM_000264.5 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.16

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]

LOC100507346 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 9-95467134-AGTA-CT is Pathogenic according to our data. Variant chr9-95467134-AGTA-CT is described in ClinVar as [Pathogenic]. Clinvar id is 218279.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTCH1	NM_000264.5	c.2539_2542delinsAG	p.Tyr847SerfsTer13	frameshift_variant	15/24	ENST00000331920.11
PTCH1	NM_001083603.3	c.2536_2539delinsAG	p.Tyr846SerfsTer13	frameshift_variant	15/24	ENST00000437951.6
LOC100507346	NR_038982.1	n.395_398delinsCT		non_coding_transcript_exon_variant	2/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTCH1	ENST00000331920.11	c.2539_2542delinsAG	p.Tyr847SerfsTer13	frameshift_variant	15/24	5	NM_000264.5	A2
PTCH1	ENST00000437951.6	c.2536_2539delinsAG	p.Tyr846SerfsTer13	frameshift_variant	15/24	5	NM_001083603.3

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:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Gorlin syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

May 22, 2015

This sequence change deletes four nucleotides and inserts 2 nucleotide in exon 15 of the PTCH1 mRNA (c.2539_2540delTACTinsAG), causing a frameshift at codon 848. This creates a premature translational stop signal (p.Phe848Glnfs*13) and is expected to result in an absent or disrupted protein product. While this particular sequence change has not been reported in the literature, truncating sequence changes in PTCH1 are known to be pathogenic (PMID: 16301862, 16419085). For these reasons, this variant has been classified as Pathogenic. -

Hereditary cancer-predisposing syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 27, 2016

The c.2539_2542delTACTinsAG pathogenic mutation, located in coding exon 15 of the PTCH1 gene, results from the deletion of four nucleotides and insertion of two nucleotides, causing a translational frameshift with a predicted alternate stop codon. Since frameshifts are typically deleterious in nature, this alteration is interpreted as a disease-causing mutation (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008;10:294). -

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: rs863225467; hg19: chr9-98229416;