9-95469098-C-G

Position:

• chr9-95469098-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000264.5(PTCH1):​c.1903G>C​(p.Asp635His) 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. 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: 2.50

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]

LOC100507346 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3387552).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PTCH1	NM_000264.5	c.1903G>C	p.Asp635His	missense_variant	14/24	ENST00000331920.11	NP_000255.2
PTCH1	NM_001083603.3	c.1900G>C	p.Asp634His	missense_variant	14/24	ENST00000437951.6	NP_001077072.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PTCH1	ENST00000331920.11	c.1903G>C	p.Asp635His	missense_variant	14/24	5	NM_000264.5	ENSP00000332353.6
PTCH1	ENST00000437951.6	c.1900G>C	p.Asp634His	missense_variant	14/24	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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 17, 2023

This sequence change replaces aspartic acid, which is acidic and polar, with histidine, which is basic and polar, at codon 635 of the PTCH1 protein (p.Asp635His). 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. 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. -

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 19, 2024

The p.D635H variant (also known as c.1903G>C), located in coding exon 14 of the PTCH1 gene, results from a G to C substitution at nucleotide position 1903. The aspartic acid at codon 635 is replaced by histidine, an amino acid with similar properties. This amino acid position is conserved. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this variant remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.039	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.67	D;.;.;.;.;.;.;.
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.31
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.89	D;.;D;D;.;.;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.34	T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.24	D
MutationAssessor	Benign	2.0	M;.;.;.;.;.;.;.
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-2.3	N;N;N;N;N;N;N;N
REVEL	Uncertain	0.41
Sift	Uncertain	0.012	D;D;D;D;D;D;D;D
Sift4G	Uncertain	0.0080	D;D;D;D;D;D;D;.
Polyphen		0.81	P;B;B;B;B;B;P;.
Vest4		0.27
MutPred		0.43		Loss of solvent accessibility (P = 0.0442);.;.;.;.;.;.;.;
MVP		0.76
MPC		1.5
ClinPred		0.78	D
GERP RS		2.7
Varity_R		0.079
gMVP		0.42

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: chr9-98231380;