rs878853853

Positions:

• chr9-95458292-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP2 PP3

The NM_000264.5(PTCH1):​c.2889C>G​(p.Ile963Met) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PTCH1 NM_000264.5 missense, splice_region
• Scores: Splicing: ADA: 0.09349
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.880

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.

• PM1: In a topological_domain Extracellular (size 257) in uniprot entity PTC1_HUMAN there are 24 pathogenic changes around while only 5 benign (83%) in NM_000264.5
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PTCH1. . Gene score misZ 1.6774 (greater than the threshold 3.09). Trascript score misZ 3.1343 (greater than threshold 3.09). GenCC has associacion of gene with holoprosencephaly 7, nevoid basal cell carcinoma syndrome, holoprosencephaly.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.784

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTCH1	NM_000264.5	c.2889C>G	p.Ile963Met	missense_variant, splice_region_variant	18/24	ENST00000331920.11	NP_000255.2
PTCH1	NM_001083603.3	c.2886C>G	p.Ile962Met	missense_variant, splice_region_variant	18/24	ENST00000437951.6	NP_001077072.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTCH1	ENST00000331920.11	c.2889C>G	p.Ile963Met	missense_variant, splice_region_variant	18/24	5	NM_000264.5	ENSP00000332353	A2
PTCH1	ENST00000437951.6	c.2886C>G	p.Ile962Met	missense_variant, splice_region_variant	18/24	5	NM_001083603.3	ENSP00000389744

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Gorlin syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 11, 2016

This sequence change replaces isoleucine with methionine at codon 963 of the PTCH1 protein (p.Ile963Met). The isoleucine residue is highly conserved and there is a small physicochemical difference between isoleucine and methionine. In summary, this is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a PTCH1-related disease. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 16, 2024

The p.I963M variant (also known as c.2889C>G), located in coding exon 18 of the PTCH1 gene, results from a C to G substitution at nucleotide position 2889. The isoleucine at codon 963 is replaced by methionine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.55	D;.;.;.;.;.;.
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.96	D;.;D;D;.;.;D
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.78	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.53	D
MutationAssessor	Benign	2.0	M;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-2.0	N;N;N;N;N;N;N
REVEL	Pathogenic	0.73
Sift	Benign	0.068	T;T;T;T;T;T;T
Sift4G	Benign	0.099	T;T;T;T;T;T;T
Polyphen		0.97	D;.;.;D;D;.;D
Vest4		0.71
MutPred		0.61		Loss of sheet (P = 0.0315);.;.;.;.;.;.;
MVP		0.75
MPC		1.3
ClinPred		0.81	D
GERP RS		3.1
Varity_R		0.44
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.093
dbscSNV1_RF	Benign	0.28
SpliceAI score (max)		0.0		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: rs878853853; hg19: chr9-98220574;