chr9-95477561-C-T
Position:
Variant summary
Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PM1PP2BP6BS2
The NM_000264.5(PTCH1):c.1489G>A(p.Ala497Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,874 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000068 ( 0 hom. )
Consequence
PTCH1
NM_000264.5 missense
NM_000264.5 missense
Scores
7
10
2
Clinical Significance
Conservation
PhyloP100: 7.39
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -2 ACMG points.
PM1
In a domain SSD (size 160) in uniprot entity PTC1_HUMAN there are 28 pathogenic changes around while only 2 benign (93%) in NM_000264.5
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), PTCH1. . Gene score misZ 1.6774 (greater than the threshold 3.09). Trascript score misZ 3.1343 (greater than threshold 3.09). GenCC has associacion of gene with holoprosencephaly 7, nevoid basal cell carcinoma syndrome, holoprosencephaly.
BP6
Variant 9-95477561-C-T is Benign according to our data. Variant chr9-95477561-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 453790.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.
BS2
High AC in GnomAdExome4 at 10 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PTCH1 | NM_000264.5 | c.1489G>A | p.Ala497Thr | missense_variant | 10/24 | ENST00000331920.11 | NP_000255.2 | |
PTCH1 | NM_001083603.3 | c.1486G>A | p.Ala496Thr | missense_variant | 10/24 | ENST00000437951.6 | NP_001077072.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PTCH1 | ENST00000331920.11 | c.1489G>A | p.Ala497Thr | missense_variant | 10/24 | 5 | NM_000264.5 | ENSP00000332353.6 | ||
PTCH1 | ENST00000437951.6 | c.1486G>A | p.Ala496Thr | missense_variant | 10/24 | 5 | NM_001083603.3 | ENSP00000389744.2 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
Cov.:
33
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251400Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135892
GnomAD3 exomes
AF:
AC:
3
AN:
251400
Hom.:
AF XY:
AC XY:
1
AN XY:
135892
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.00000684 AC: 10AN: 1461874Hom.: 0 Cov.: 32 AF XY: 0.00000688 AC XY: 5AN XY: 727238
GnomAD4 exome
AF:
AC:
10
AN:
1461874
Hom.:
Cov.:
32
AF XY:
AC XY:
5
AN XY:
727238
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome Cov.: 33
GnomAD4 genome
Cov.:
33
Bravo
AF:
ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Jul 11, 2023 | In the published literature, this variant has been reported in an individual with polydactyly (PMID: 34194672 (2021)). The frequency of this variant in the general population, 0.000087 (3/34590 chromosomes in Latino/Admixed American subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. - |
Hereditary cancer-predisposing syndrome Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Dec 04, 2023 | The p.A497T variant (also known as c.1489G>A), located in coding exon 10 of the PTCH1 gene, results from a G to A substitution at nucleotide position 1489. The alanine at codon 497 is replaced by threonine, an amino acid with similar properties. This variant was described in 1 of 181 Chinese individuals with polydactyly (Zu B et al. Comput Struct Biotechnol J, 2021 Jun;19:3482-3490). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. - |
Gorlin syndrome Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 29, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
D;.;.;.;.;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;.;D;D;.;.;D
M_CAP
Uncertain
D
MetaRNN
Uncertain
D;D;D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Benign
L;.;.;.;.;.;.
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;D;D;D;D;D;D
REVEL
Pathogenic
Sift
Uncertain
D;D;D;D;D;D;D
Sift4G
Pathogenic
D;D;D;D;D;D;D
Polyphen
D;.;.;D;D;.;D
Vest4
MutPred
Gain of helix (P = 0.0696);.;.;.;.;.;.;
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at