9-95447232-G-C

Variant names:

• chr9-95447232-G-C
• NM_000264.5:c.4024C>G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000264.5(PTCH1):​c.4024C>G​(p.Arg1342Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1342H) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: PTCH1 NM_000264.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.50

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20896715).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTCH1	NM_000264.5	c.4024C>G	p.Arg1342Gly	missense_variant	Exon 23 of 24	ENST00000331920.11	NP_000255.2
PTCH1	NM_001083603.3	c.4021C>G	p.Arg1341Gly	missense_variant	Exon 23 of 24	ENST00000437951.6	NP_001077072.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTCH1	ENST00000331920.11	c.4024C>G	p.Arg1342Gly	missense_variant	Exon 23 of 24	5	NM_000264.5	ENSP00000332353.6
PTCH1	ENST00000437951.6	c.4021C>G	p.Arg1341Gly	missense_variant	Exon 23 of 24	5	NM_001083603.3	ENSP00000389744.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Gorlin syndrome Uncertain:1

Jun 12, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. 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. This variant has not been reported in the literature in individuals with PTCH1-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with glycine at codon 1342 of the PTCH1 protein (p.Arg1342Gly). The arginine residue is weakly conserved and there is a moderate physicochemical difference between arginine and glycine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Uncertain	0.035	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	17
DANN	Benign	0.97
DEOGEN2	Benign	0.25	T;.;.;.;.;.;.
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.26
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.80	T;.;T;T;.;.;T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.21	T;T;T;T;T;T;T
MetaSVM	Uncertain	0.21	D
MutationAssessor	Benign	1.9	L;.;.;.;.;.;.
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.92	N;N;N;N;N;N;N
REVEL	Uncertain	0.34
Sift	Uncertain	0.0070	D;D;D;D;D;D;D
Sift4G	Uncertain	0.044	D;D;D;D;D;D;D
Polyphen		0.049	B;.;.;B;B;.;B
Vest4		0.41
MutPred		0.27		Loss of methylation at R1342 (P = 0.0219);.;.;.;.;.;.;
MVP		0.56
MPC		0.098
ClinPred		0.31	T
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.10
gMVP		0.31

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-98209514;