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GeneBe

9-95508175-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_000264.5(PTCH1):c.187G>C(p.Glu63Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,460,568 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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. E63D) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

PTCH1
NM_000264.5 missense

Scores

1
2
16

Clinical Significance

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

Conservation

PhyloP100: 5.19
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 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant where missense usually causes diseases, PTCH1
BP4
Computational evidence support a benign effect (MetaRNN=0.1339367).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
PTCH1NM_000264.5 linkuse as main transcriptc.187G>C p.Glu63Gln missense_variant 1/24 ENST00000331920.11
PTCH1NM_001083603.3 linkuse as main transcriptc.199-1576G>C intron_variant ENST00000437951.6

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
PTCH1ENST00000331920.11 linkuse as main transcriptc.187G>C p.Glu63Gln missense_variant 1/245 NM_000264.5 A2Q13635-1
PTCH1ENST00000437951.6 linkuse as main transcriptc.199-1576G>C intron_variant 5 NM_001083603.3 Q13635-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000403
AC:
1
AN:
248420
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135070
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000896
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1460568
Hom.:
0
Cov.:
34
AF XY:
0.00000138
AC XY:
1
AN XY:
726636
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.0000383
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
ExAC
AF:
0.00000824
AC:
1

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 testingInvitaeJan 23, 2020In 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 (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with PTCH1-related conditions. This variant is present in population databases (rs781768965, ExAC 0.002%). This sequence change replaces glutamic acid with glutamine at codon 63 of the PTCH1 protein (p.Glu63Gln). The glutamic acid residue is weakly conserved and there is a small physicochemical difference between glutamic acid and glutamine. -
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsFeb 23, 2024The p.E63Q variant (also known as c.187G>C), located in coding exon 1 of the PTCH1 gene, results from a G to C substitution at nucleotide position 187. The glutamic acid at codon 63 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. Based on the available evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.088
BayesDel_addAF
Benign
0.0036
T
BayesDel_noAF
Benign
-0.23
Cadd
Benign
22
Dann
Benign
0.93
DEOGEN2
Benign
0.24
T
Eigen
Benign
-0.38
Eigen_PC
Benign
-0.19
FATHMM_MKL
Uncertain
0.83
D
LIST_S2
Uncertain
0.86
D
M_CAP
Benign
0.084
D
MetaRNN
Benign
0.13
T
MetaSVM
Benign
-0.79
T
MutationAssessor
Benign
-0.030
N
MutationTaster
Benign
1.0
D;D;D;D;D
PrimateAI
Pathogenic
0.87
D
PROVEAN
Benign
-0.48
N
REVEL
Benign
0.18
Sift
Benign
0.26
T
Sift4G
Benign
0.47
T
Polyphen
0.010
B
Vest4
0.16
MutPred
0.20
Loss of ubiquitination at K67 (P = 0.0245);
MVP
0.58
MPC
0.54
ClinPred
0.40
T
GERP RS
3.4
Varity_R
0.32
gMVP
0.51

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: rs781768965; hg19: chr9-98270457; API