rs1554698774

Positions:

• chr9-95478054-CCAT-C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PM4_Supporting PP3_Moderate

The NM_000264.5(PTCH1):​c.1345_1347del​(p.Met449del) variant causes a inframe deletion, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTCH1 NM_000264.5 inframe_deletion, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.95

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 7 ACMG points.

• PM1: In a transmembrane_region Helical (size 20) in uniprot entity PTC1_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_000264.5
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000264.5. Strenght limited to Supporting due to length of the change: 1aa.
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTCH1	NM_000264.5	c.1345_1347del	p.Met449del	inframe_deletion, splice_region_variant	9/24	ENST00000331920.11	NP_000255.2
PTCH1	NM_001083603.3	c.1342_1344del	p.Met448del	inframe_deletion, splice_region_variant	9/24	ENST00000437951.6	NP_001077072.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTCH1	ENST00000331920.11	c.1345_1347del	p.Met449del	inframe_deletion, splice_region_variant	9/24	5	NM_000264.5	ENSP00000332353	A2
PTCH1	ENST00000437951.6	c.1342_1344del	p.Met448del	inframe_deletion, splice_region_variant	9/24	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: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Gorlin syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 30, 2020

This variant, c.1345_1347delATG, results in the deletion of 1 amino acid of the PTCH1 protein (p.Met449del), but otherwise preserves the integrity of the reading frame. This variant also affects the last nucleotide of exon 9 of the PTCH1 coding sequence, which is part of the consensus splice site for this exon. 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. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). 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. This variant has been observed in a family affected with Gorlin syndrome (Invitae). This variant also has been reported in an individual affected with Gorlin syndrome (Gilbert, A., American Association of Neuropathologist Annual Meeting, 2016). This variant is not present in population databases (ExAC no frequency). -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.56		Position offset: 4
DS_DL_spliceai		1.0		Position offset: 1

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

Publications

LitVar

Other links and lift over

dbSNP: rs1554698774; hg19: chr9-98240336;