9-95508252-C-G

Variant names:

• chr9-95508252-C-G
• rs748780206
• NM_000264.5:c.110G>C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_000264.5(PTCH1):​c.110G>C​(p.Gly37Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G37R) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTCH1 NM_000264.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 2.40

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_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19815132).
• BP6: Variant 9-95508252-C-G is Benign according to our data. Variant chr9-95508252-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 822183.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTCH1	NM_000264.5	c.110G>C	p.Gly37Ala	missense_variant	Exon 1 of 24	ENST00000331920.11	NP_000255.2
PTCH1	NM_001083603.3	c.199-1653G>C		intron_variant	Intron 1 of 23	ENST00000437951.6	NP_001077072.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTCH1	ENST00000331920.11	c.110G>C	p.Gly37Ala	missense_variant	Exon 1 of 24	5	NM_000264.5	ENSP00000332353.6
PTCH1	ENST00000437951.6	c.199-1653G>C		intron_variant	Intron 1 of 23	5	NM_001083603.3	ENSP00000389744.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Gorlin syndrome Uncertain:1

Feb 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 37 of the PTCH1 protein (p.Gly37Ala). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with PTCH1-related conditions. ClinVar contains an entry for this variant (Variation ID: 822183). 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 with a negative predictive value of 95%. 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. -

Hereditary cancer-predisposing syndrome Uncertain:1

Nov 15, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.G37A variant (also known as c.110G>C), located in coding exon 1 of the PTCH1 gene, results from a G to C substitution at nucleotide position 110. The glycine at codon 37 is replaced by alanine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Breast carcinoma Benign:1

Jan 01, 2019

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.076	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	9.8
DANN	Benign	0.58
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.97
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.58	T
M_CAP	Pathogenic	0.87	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	1.1	L
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	0.14	N
REVEL	Benign	0.20
Sift	Benign	0.83	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.13
MutPred		0.18		Loss of loop (P = 0.0073);
MVP		0.57
MPC		1.3
ClinPred		0.076	T
GERP RS		-0.36
Varity_R		0.026
gMVP		0.53

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: rs748780206; hg19: chr9-98270534;