9-95508325-G-A

Position:

• chr9-95508325-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_000264.5(PTCH1):​c.37C>T​(p.Arg13Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000339 in 1,179,392 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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. R13G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: PTCH1 NM_000264.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: -1.28

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 1 ACMG points.

• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.22267309).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PTCH1	NM_000264.5	c.37C>T	p.Arg13Cys	missense_variant	1/24	ENST00000331920.11
PTCH1	NM_001083603.3	c.199-1726C>T		intron_variant		ENST00000437951.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PTCH1	ENST00000331920.11	c.37C>T	p.Arg13Cys	missense_variant	1/24	5	NM_000264.5	A2
PTCH1	ENST00000437951.6	c.199-1726C>T		intron_variant		5	NM_001083603.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000339 AC: 4 AN: 1179392 Hom.: 0 Cov.: 33 AF XY: 0.00000175 AC XY: 1 AN XY: 571788

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000109

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000307

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Basal cell carcinoma, susceptibility to, 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Apr 04, 2019

This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PM2. This variant was detected in homozygous state. -

Gorlin syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jun 29, 2022

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 13 of the PTCH1 protein (p.Arg13Cys). 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. ClinVar contains an entry for this variant (Variation ID: 930369). This variant has not been reported in the literature in individuals affected with PTCH1-related conditions. This variant is not present in population databases (gnomAD no frequency). -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 21, 2023

The p.R13C variant (also known as c.37C>T), located in coding exon 1 of the PTCH1 gene, results from a C to T substitution at nucleotide position 37. The arginine at codon 13 is replaced by cysteine, an amino acid with highly dissimilar properties. This amino acid position is poorly 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.078	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.67	T
M_CAP	Pathogenic	0.89	D
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.48	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	D;D;D;D;N
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.23
Sift	Benign	0.066	T
Sift4G	Benign	0.20	T
Polyphen		0.35	B
Vest4		0.088
MutPred		0.22		Loss of MoRF binding (P = 0.078);
MVP		0.45
MPC		0.74
ClinPred		0.16	T
GERP RS		1.4
Varity_R		0.11
gMVP		0.32

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: rs779791579; hg19: chr9-98270607;