rs878853847

Positions:

• chr9-95476146-TC-T
• chr9-95476146-TC-TCC

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000264.5(PTCH1):​c.1615del​(p.Glu539SerfsTer3) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). 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: 4.58

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 Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-95476146-TC-T is Pathogenic according to our data. Variant chr9-95476146-TC-T is described in ClinVar as [Pathogenic]. Clinvar id is 237457.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-95476146-TC-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTCH1	NM_000264.5	c.1615del	p.Glu539SerfsTer3	frameshift_variant	12/24	ENST00000331920.11
PTCH1	NM_001083603.3	c.1612del	p.Glu538SerfsTer3	frameshift_variant	12/24	ENST00000437951.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTCH1	ENST00000331920.11	c.1615del	p.Glu539SerfsTer3	frameshift_variant	12/24	5	NM_000264.5	A2
PTCH1	ENST00000437951.6	c.1612del	p.Glu538SerfsTer3	frameshift_variant	12/24	5	NM_001083603.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

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

Oct 04, 2020

For these reasons, this variant has been classified as Pathogenic. Truncating variants in PTCH1 are known to be pathogenic. This particular truncation has been reported to segregate with Gorlin syndrome in a single family (PMID: 15459969). It was seen in 4 family members, with phenotypes of nevoid basal cell carcinoma, jaw cysts, and eye anomalies. This sequence change deletes 1 nucleotide from exon 12 of the PTCH1 mRNA (c.1615delG), causing a frameshift at codon 539. This creates a premature translational stop signal (p.Glu539Serfs*3) and is expected to result in an absent or disrupted protein product. -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Aug 19, 2016

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs878853847; hg19: chr9-98238428;