9-95449290-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PM1PM2PM5BP4

The NM_000264.5(PTCH1):​c.3583A>G​(p.Thr1195Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000213 in 1,405,206 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. T1195S) has been classified as Benign.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

PTCH1
NM_000264.5 missense

Scores

14
5

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.02
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 5 ACMG points.

PM1
In a modified_residue Phosphothreonine (size 0) in uniprot entity PTC1_HUMAN
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr9-95449290-T-A is described in Lovd as [Pathogenic].
BP4
Computational evidence support a benign effect (MetaRNN=0.33502173).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PTCH1NM_000264.5 linkc.3583A>G p.Thr1195Ala missense_variant Exon 22 of 24 ENST00000331920.11 NP_000255.2 Q13635-1
PTCH1NM_001083603.3 linkc.3580A>G p.Thr1194Ala missense_variant Exon 22 of 24 ENST00000437951.6 NP_001077072.1 Q13635-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
PTCH1ENST00000331920.11 linkc.3583A>G p.Thr1195Ala missense_variant Exon 22 of 24 5 NM_000264.5 ENSP00000332353.6 Q13635-1
PTCH1ENST00000437951.6 linkc.3580A>G p.Thr1194Ala missense_variant Exon 22 of 24 5 NM_001083603.3 ENSP00000389744.2 Q13635-2

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000213
AC:
3
AN:
1405206
Hom.:
0
Cov.:
31
AF XY:
0.00000432
AC XY:
3
AN XY:
693956
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000375
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1
Sep 01, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.T1195A variant (also known as c.3583A>G), located in coding exon 22 of the PTCH1 gene, results from an A to G substitution at nucleotide position 3583. The threonine at codon 1195 is replaced by alanine, an amino acid with similar properties. This amino acid position is conserved. In addition, the in silico prediction for this alteration is inconclusive. 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
0.086
BayesDel_addAF
Uncertain
0.13
D
BayesDel_noAF
Uncertain
-0.050
CADD
Benign
21
DANN
Uncertain
0.98
DEOGEN2
Uncertain
0.74
D;.;.;.;.;.;.
Eigen
Benign
0.12
Eigen_PC
Benign
0.22
FATHMM_MKL
Uncertain
0.94
D
LIST_S2
Uncertain
0.95
D;.;D;D;.;.;D
M_CAP
Uncertain
0.19
D
MetaRNN
Benign
0.34
T;T;T;T;T;T;T
MetaSVM
Uncertain
0.013
D
MutationAssessor
Uncertain
2.3
M;.;.;.;.;.;.
PrimateAI
Uncertain
0.51
T
PROVEAN
Uncertain
-2.5
N;N;N;N;N;N;D
REVEL
Uncertain
0.42
Sift
Uncertain
0.0080
D;D;D;D;D;D;D
Sift4G
Uncertain
0.026
D;D;D;D;D;D;D
Polyphen
0.47
P;.;.;B;B;.;P
Vest4
0.44
MutPred
0.28
Loss of glycosylation at T1195 (P = 3e-04);.;.;.;.;.;.;
MVP
0.86
MPC
0.59
ClinPred
0.92
D
GERP RS
4.6
Varity_R
0.22
gMVP
0.74

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: chr9-98211572; API