chr9-95467181-A-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_ModeratePP5_Moderate

The NM_000264.5(PTCH1):​c.2495T>A​(p.Val832Asp) 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V832I) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Consequence

PTCH1
NM_000264.5 missense

Scores

12
6
1

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 8.95

Publications

1 publications found
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]
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

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.908
PP5
Variant 9-95467181-A-T is Pathogenic according to our data. Variant chr9-95467181-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 188235.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
PTCH1NM_000264.5 linkc.2495T>A p.Val832Asp missense_variant Exon 15 of 24 ENST00000331920.11 NP_000255.2 Q13635-1
PTCH1NM_001083603.3 linkc.2492T>A p.Val831Asp missense_variant Exon 15 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.2495T>A p.Val832Asp missense_variant Exon 15 of 24 5 NM_000264.5 ENSP00000332353.6 Q13635-1
PTCH1ENST00000437951.6 linkc.2492T>A p.Val831Asp missense_variant Exon 15 of 24 5 NM_001083603.3 ENSP00000389744.2 Q13635-2

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
33
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Gorlin syndrome Pathogenic:1
Nov 13, 2019
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

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 disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This sequence change replaces valine with aspartic acid at codon 832 of the PTCH1 protein (p.Val832Asp). The valine residue is moderately conserved and there is a large physicochemical difference between valine and aspartic acid. This variant is not present in population databases (ExAC no frequency). This variant has been observed to segregate with clinical features of nevoid basal cell carcinoma syndrome in a family (Invitae). ClinVar contains an entry for this variant (Variation ID: 188235). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.97
BayesDel_addAF
Pathogenic
0.43
D
BayesDel_noAF
Pathogenic
0.39
CADD
Pathogenic
26
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.90
D;.;.;.;.;.;.
Eigen
Pathogenic
0.78
Eigen_PC
Pathogenic
0.76
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.96
D;.;D;D;.;.;D
M_CAP
Uncertain
0.28
D
MetaRNN
Pathogenic
0.91
D;D;D;D;D;D;D
MetaSVM
Uncertain
0.51
D
MutationAssessor
Uncertain
2.7
M;.;.;.;.;.;.
PhyloP100
8.9
PrimateAI
Uncertain
0.70
T
PROVEAN
Pathogenic
-5.8
D;D;D;D;D;D;D
REVEL
Pathogenic
0.91
Sift
Pathogenic
0.0
D;D;D;D;D;D;D
Sift4G
Pathogenic
0.0010
D;D;D;D;D;D;D
Polyphen
1.0
D;.;.;D;D;.;D
Vest4
0.90
MutPred
0.73
Loss of sheet (P = 0.0126);.;.;.;.;.;.;
MVP
0.92
MPC
1.9
ClinPred
1.0
D
GERP RS
5.5
Varity_R
0.95
gMVP
0.98
Mutation Taster
=9/91
disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs786204167; hg19: chr9-98229463; API