9-95449234-G-C

Variant names:

• chr9-95449234-G-C
• NM_000264.5:c.3639C>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.3639C>G​(p.His1213Gln) 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. 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. H1213N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: PTCH1 NM_000264.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.00

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=0.20125204).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTCH1	NM_000264.5	c.3639C>G	p.His1213Gln	missense_variant	Exon 22 of 24	ENST00000331920.11	NP_000255.2
PTCH1	NM_001083603.3	c.3636C>G	p.His1212Gln	missense_variant	Exon 22 of 24	ENST00000437951.6	NP_001077072.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PTCH1	ENST00000331920.11	c.3639C>G	p.His1213Gln	missense_variant	Exon 22 of 24	5	NM_000264.5	ENSP00000332353.6
PTCH1	ENST00000437951.6	c.3636C>G	p.His1212Gln	missense_variant	Exon 22 of 24	5	NM_001083603.3	ENSP00000389744.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

May 28, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.H1213Q variant (also known as c.3639C>G), located in coding exon 22 of the PTCH1 gene, results from a C to G substitution at nucleotide position 3639. The histidine at codon 1213 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is conserved. 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	0.097
BayesDel_addAF	Uncertain	0.024	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	3.9
DANN	Benign	0.78
DEOGEN2	Benign	0.29	T;.;.;.;.;.;.
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.47
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.76	T;.;T;T;.;.;T
M_CAP	Benign	0.032	D
MetaRNN	Benign	0.20	T;T;T;T;T;T;T
MetaSVM	Benign	-0.32	T
MutationAssessor	Uncertain	2.3	M;.;.;.;.;.;.
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.2	N;N;N;N;N;N;N
REVEL	Uncertain	0.34
Sift	Benign	0.32	T;T;T;T;T;T;T
Sift4G	Benign	0.23	T;T;T;T;T;T;T
Polyphen		0.30	B;.;.;P;P;.;D
Vest4		0.18
MutPred		0.11		Loss of catalytic residue at H1213 (P = 0.0685);.;.;.;.;.;.;
MVP		0.68
MPC		0.077
ClinPred		0.62	D
GERP RS		1.6
Varity_R		0.048
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: chr9-98211516;