X-23335009-G-A
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Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The ENST00000379361.5(PTCHD1):c.134G>A(p.Arg45His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,097,642 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.0 ( 0 hom., 0 hem., cov: 23)
Exomes 𝑓: 9.1e-7 ( 0 hom. 0 hem. )
Failed GnomAD Quality Control
Consequence
PTCHD1
ENST00000379361.5 missense
ENST00000379361.5 missense
Scores
7
4
6
Clinical Significance
Conservation
PhyloP100: 7.36
Genes affected
PTCHD1 (HGNC:26392): (patched domain containing 1) This gene encodes a membrane protein with a patched domain. The encoded protein is similar to Drosophila proteins which act as receptors for the morphogen sonic hedgehog. Deletions in this gene, which is located on the X chromosome, are associated with intellectual disability and autism (PMID: 21091464, PMID: 20844286). [provided by RefSeq, Aug 2011]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
PTCHD1 | NM_173495.3 | c.134G>A | p.Arg45His | missense_variant | 1/3 | ENST00000379361.5 | NP_775766.2 | |
PTCHD1 | XM_011545449.4 | c.134G>A | p.Arg45His | missense_variant | 2/4 | XP_011543751.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
PTCHD1 | ENST00000379361.5 | c.134G>A | p.Arg45His | missense_variant | 1/3 | 1 | NM_173495.3 | ENSP00000368666 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00 AC: 0AN: 111236Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0AN XY: 33460 FAILED QC
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GnomAD3 exomes AF: 0.00000556 AC: 1AN: 180015Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 66421
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GnomAD4 exome AF: 9.11e-7 AC: 1AN: 1097642Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 363080
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GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 111236Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0AN XY: 33460
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 31, 2024 | Variant summary: PTCHD1 c.134G>A (p.Arg45His) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-06 in 180015 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.134G>A has been reported in the literature in an individual affected with autism spectrum disorder without strong evidence of causality (Adbi_2023). These reports do not provide unequivocal conclusions about association of the variant with Autism, Susceptibility To, X-Linked 4. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 37805537). No submitters have cited clinical-significance assessments for this variant to ClinVar. Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Benign
T
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D
M_CAP
Pathogenic
D
MetaRNN
Uncertain
T
MetaSVM
Uncertain
T
MutationAssessor
Benign
L
MutationTaster
Benign
D
PrimateAI
Pathogenic
D
PROVEAN
Benign
N
REVEL
Pathogenic
Sift
Benign
T
Sift4G
Pathogenic
D
Polyphen
P
Vest4
MutPred
Loss of sheet (P = 0.0315);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at