9-95508204-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_000264.5(PTCH1):​c.158C>A​(p.Pro53His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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

Scores

8
9
2

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 8.79
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.831

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PTCH1NM_000264.5 linkc.158C>A p.Pro53His missense_variant 1/24 ENST00000331920.11 NP_000255.2 Q13635-1
PTCH1NM_001083603.3 linkc.199-1605C>A intron_variant ENST00000437951.6 NP_001077072.1 Q13635-2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PTCH1ENST00000331920.11 linkc.158C>A p.Pro53His missense_variant 1/245 NM_000264.5 ENSP00000332353.6 Q13635-1
PTCH1ENST00000437951.6 linkc.199-1605C>A intron_variant 5 NM_001083603.3 ENSP00000389744.2 Q13635-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
34
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Gorlin syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpSep 29, 2019In 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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 proline with histidine at codon 53 of the PTCH1 protein (p.Pro53His). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and histidine. -
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJul 27, 2021The p.P53H variant (also known as c.158C>A), located in coding exon 1 of the PTCH1 gene, results from a C to A substitution at nucleotide position 158. The proline at codon 53 is replaced by histidine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious 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
Pathogenic
0.97
BayesDel_addAF
Pathogenic
0.26
D
BayesDel_noAF
Pathogenic
0.14
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.75
D
Eigen
Uncertain
0.67
Eigen_PC
Uncertain
0.60
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Benign
0.85
T
M_CAP
Pathogenic
0.58
D
MetaRNN
Pathogenic
0.83
D
MetaSVM
Uncertain
0.49
D
MutationAssessor
Uncertain
2.6
M
PrimateAI
Pathogenic
0.93
D
PROVEAN
Uncertain
-2.6
D
REVEL
Pathogenic
0.71
Sift
Uncertain
0.0020
D
Sift4G
Uncertain
0.046
D
Polyphen
1.0
D
Vest4
0.64
MutPred
0.50
Loss of disorder (P = 0.0972);
MVP
0.61
MPC
1.6
ClinPred
0.99
D
GERP RS
3.7
Varity_R
0.92
gMVP
0.80

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs372546614; hg19: chr9-98270486; API