X-23335009-G-A

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

Scores

7
4
6

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.36
Variant links:
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]

Genome browser will be placed here

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
PTCHD1NM_173495.3 linkuse as main transcriptc.134G>A p.Arg45His missense_variant 1/3 ENST00000379361.5 NP_775766.2
PTCHD1XM_011545449.4 linkuse as main transcriptc.134G>A p.Arg45His missense_variant 2/4 XP_011543751.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PTCHD1ENST00000379361.5 linkuse as main transcriptc.134G>A p.Arg45His missense_variant 1/31 NM_173495.3 ENSP00000368666 P1Q96NR3-1

Frequencies

GnomAD3 genomes
AF:
0.00
AC:
0
AN:
111236
Hom.:
0
Cov.:
23
AF XY:
0.00
AC XY:
0
AN XY:
33460
FAILED QC
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000556
AC:
1
AN:
180015
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
66421
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:
0.0000527
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
9.11e-7
AC:
1
AN:
1097642
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
363080
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:
0.0000185
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
111236
Hom.:
0
Cov.:
23
AF XY:
0.00
AC XY:
0
AN XY:
33460
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378

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 submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpJul 31, 2024Variant 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.19
BayesDel_addAF
Pathogenic
0.28
D
BayesDel_noAF
Pathogenic
0.31
CADD
Pathogenic
26
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.064
T
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.91
D
M_CAP
Pathogenic
0.78
D
MetaRNN
Uncertain
0.47
T
MetaSVM
Uncertain
-0.085
T
MutationAssessor
Benign
1.2
L
MutationTaster
Benign
1.0
D
PrimateAI
Pathogenic
0.87
D
PROVEAN
Benign
-1.3
N
REVEL
Pathogenic
0.73
Sift
Benign
0.20
T
Sift4G
Pathogenic
0.0
D
Polyphen
0.90
P
Vest4
0.23
MutPred
0.61
Loss of sheet (P = 0.0315);
MVP
0.98
MPC
1.7
ClinPred
0.60
D
GERP RS
4.5
Varity_R
0.24
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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1365872462; hg19: chrX-23353126; COSMIC: COSV65060409; COSMIC: COSV65060409; API