9-95447022-G-C

Variant names:

• chr9-95447022-G-C
• rs1554688130
• NM_000264.5:c.4234C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000264.5(PTCH1):​c.4234C>G​(p.Pro1412Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. P1412S) has been classified 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: 7.75
• Publications: 0 publications found

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]

PTCH1 Gene-Disease associations (from GenCC):

• basal cell nevus syndrome 1

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• holoprosencephaly 7

  Inheritance: AD Classification: DEFINITIVE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• nevoid basal cell carcinoma syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet
• holoprosencephaly

  Inheritance: AD Classification: LIMITED Submitted by: Illumina

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PTCH1	NM_000264.5	c.4234C>G	p.Pro1412Ala	missense_variant	Exon 23 of 24	ENST00000331920.11	NP_000255.2
PTCH1	NM_001083603.3	c.4231C>G	p.Pro1411Ala	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.4234C>G	p.Pro1412Ala	missense_variant	Exon 23 of 24	5	NM_000264.5	ENSP00000332353.6
PTCH1	ENST00000437951.6	c.4231C>G	p.Pro1411Ala	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:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Gorlin syndrome Uncertain:1

Feb 28, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a PTCH1-related disease. This sequence change replaces proline with alanine at codon 1412 of the PTCH1 protein (p.Pro1412Ala). The proline residue is moderately conserved and there is a small physicochemical difference between proline and alanine. -

Hereditary cancer-predisposing syndrome Uncertain:1

Nov 26, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.P1412A variant (also known as c.4234C>G), located in coding exon 23 of the PTCH1 gene, results from a C to G substitution at nucleotide position 4234. The proline at codon 1412 is replaced by alanine, an amino acid with highly similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. 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	0.29
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	T;.;.;.;.;.;.
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;.;D;D;.;.;D
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.63	D;D;D;D;D;D;D
MetaSVM	Uncertain	0.65	D
MutationAssessor	Benign	2.0	M;.;.;.;.;.;.
PhyloP100		7.7
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.95	N;N;N;N;N;N;N
REVEL	Uncertain	0.61
Sift	Benign	0.16	T;T;T;T;T;T;T
Sift4G	Benign	0.13	T;T;T;T;T;T;T
Polyphen		1.0	D;.;.;D;D;.;D
Vest4		0.74
MutPred		0.47		Loss of disorder (P = 0.0922);.;.;.;.;.;.;
MVP		0.43
MPC		0.40
ClinPred		0.90	D
GERP RS		5.1
Varity_R		0.17
gMVP		0.59
Mutation Taster		=54/46	polymorphism

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

Other links and lift over

dbSNP: rs1554688130; hg19: chr9-98209304;