rs864622160

Variant names:

• chr9-95449863-G-C
• rs864622160
• NM_000264.5:c.3527C>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_000264.5(PTCH1):​c.3527C>G​(p.Ser1176Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PTCH1 NM_000264.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 10.0

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.881

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTCH1	NM_000264.5	c.3527C>G	p.Ser1176Cys	missense_variant	Exon 21 of 24	ENST00000331920.11	NP_000255.2
PTCH1	NM_001083603.3	c.3524C>G	p.Ser1175Cys	missense_variant	Exon 21 of 24	ENST00000437951.6	NP_001077072.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTCH1	ENST00000331920.11	c.3527C>G	p.Ser1176Cys	missense_variant	Exon 21 of 24	5	NM_000264.5	ENSP00000332353.6
PTCH1	ENST00000437951.6	c.3524C>G	p.Ser1175Cys	missense_variant	Exon 21 of 24	5	NM_001083603.3	ENSP00000389744.2

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

Jul 19, 2015

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is not present in population databases and has not been published in the literature. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. This sequence change replaces serine with cysteine at codon 1176 of the PTCH1 protein (p.Ser1176Cys). The serine residue is highly conserved and there is a moderate physicochemical difference between serine and cysteine. In summary, this is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. -

Hereditary cancer-predisposing syndrome Uncertain:1

Feb 17, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.S1176C variant (also known as c.3527C>G), located in coding exon 21 of the PTCH1 gene, results from a C to G substitution at nucleotide position 3527. The serine at codon 1176 is replaced by cysteine, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.88	D;.;.;.;.;.;.
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;.;D;D;.;.;D
M_CAP	Uncertain	0.23	D
MetaRNN	Pathogenic	0.88	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.79	D
MutationAssessor	Uncertain	2.8	M;.;.;.;.;.;.
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-3.9	D;D;D;D;D;D;D
REVEL	Pathogenic	0.83
Sift	Pathogenic	0.0	D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D
Polyphen		1.0	D;.;.;D;D;.;D
Vest4		0.85
MutPred		0.66		Loss of helix (P = 0.0558);.;.;.;.;.;.;
MVP		0.86
MPC		1.5
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.93
gMVP		0.83

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: rs864622160; hg19: chr9-98212145;