9-95468863-G-C

Variant names:

• chr9-95468863-G-C
• rs1554694963
• NM_000264.5:c.2138C>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000264.5(PTCH1):​c.2138C>G​(p.Ser713Cys) 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: 32)
• Consequence: PTCH1 NM_000264.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 9.44

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.759

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTCH1	NM_000264.5	c.2138C>G	p.Ser713Cys	missense_variant	Exon 14 of 24	ENST00000331920.11	NP_000255.2
PTCH1	NM_001083603.3	c.2135C>G	p.Ser712Cys	missense_variant	Exon 14 of 24	ENST00000437951.6	NP_001077072.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTCH1	ENST00000331920.11	c.2138C>G	p.Ser713Cys	missense_variant	Exon 14 of 24	5	NM_000264.5	ENSP00000332353.6
PTCH1	ENST00000437951.6	c.2135C>G	p.Ser712Cys	missense_variant	Exon 14 of 24	5	NM_001083603.3	ENSP00000389744.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Gorlin syndrome Uncertain:1

Mar 05, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ClinVar contains an entry for this variant (Variation ID: 524518). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt PTCH1 protein function. 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. This variant has not been reported in the literature in individuals affected with PTCH1-related conditions. This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 713 of the PTCH1 protein (p.Ser713Cys). This variant is not present in population databases (gnomAD no frequency). -

not provided Uncertain:1

Jun 08, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 11331587) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.57	D;.;.;.;.;.;.
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.91	D;.;D;D;.;.;D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.76	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.34	D
MutationAssessor	Uncertain	2.1	M;.;.;.;.;.;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-1.3	N;N;N;N;N;N;N
REVEL	Pathogenic	0.73
Sift	Benign	0.13	T;T;T;T;T;T;T
Sift4G	Benign	0.14	T;T;T;T;T;T;T
Polyphen		0.85	P;P;P;P;P;P;D
Vest4		0.78
MutPred		0.48		Gain of sheet (P = 0.0061);.;.;.;.;.;.;
MVP		0.52
MPC		1.3
ClinPred		0.94	D
GERP RS		4.8
Varity_R		0.23
gMVP		0.61

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs1554694963; hg19: chr9-98231145;