rs137852214
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_016032.4(ZDHHC9):c.442C>T(p.Arg148Trp) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/20 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 24)
Consequence
ZDHHC9
NM_016032.4 missense
NM_016032.4 missense
Scores
12
4
1
Clinical Significance
Conservation
PhyloP100: 6.11
Genes affected
ZDHHC9 (HGNC:18475): (zinc finger DHHC-type palmitoyltransferase 9) This gene encodes an integral membrane protein that is a member of the zinc finger DHHC domain-containing protein family. The encoded protein forms a complex with golgin subfamily A member 7 and functions as a palmitoyltransferase. This protein specifically palmitoylates HRAS and NRAS. Mutations in this gene are associated with X-linked cognitive disability. Alternate splicing results in multiple transcript variants that encode the same protein.[provided by RefSeq, May 2010]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.98
PP5
Variant X-129823724-G-A is Pathogenic according to our data. Variant chrX-129823724-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 10711.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-129823724-G-A is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ZDHHC9 | NM_016032.4 | c.442C>T | p.Arg148Trp | missense_variant | 5/11 | ENST00000357166.11 | NP_057116.2 | |
ZDHHC9 | NM_001008222.3 | c.442C>T | p.Arg148Trp | missense_variant | 4/10 | NP_001008223.1 | ||
ZDHHC9 | XM_047442151.1 | c.442C>T | p.Arg148Trp | missense_variant | 5/8 | XP_047298107.1 | ||
ZDHHC9 | XM_011531348.4 | c.442C>T | p.Arg148Trp | missense_variant | 5/6 | XP_011529650.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ZDHHC9 | ENST00000357166.11 | c.442C>T | p.Arg148Trp | missense_variant | 5/11 | 1 | NM_016032.4 | ENSP00000349689.6 |
Frequencies
GnomAD3 genomes Cov.: 24
GnomAD3 genomes
Cov.:
24
GnomAD4 exome Cov.: 33
GnomAD4 exome
Cov.:
33
GnomAD4 genome Cov.: 24
GnomAD4 genome
Cov.:
24
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Syndromic X-linked intellectual disability Raymond type Pathogenic:4
Likely pathogenic, criteria provided, single submitter | clinical testing | Centre for Mendelian Genomics, University Medical Centre Ljubljana | Jan 01, 2016 | This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM2,PP2,PP3. This variant was detected in hemizygous state. - |
Pathogenic, criteria provided, single submitter | clinical testing | Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen | Oct 21, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Apr 12, 2023 | Experimental studies have shown that this missense change affects ZDHHC9 function (PMID: 24811172). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt ZDHHC9 protein function. ClinVar contains an entry for this variant (Variation ID: 10711). This missense change has been observed in individual(s) with X-linked intellectual disability (PMID: 17436253, 29681091). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 148 of the ZDHHC9 protein (p.Arg148Trp). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 2007 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2020 | - - |
Intellectual disability Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Diagnostic Laboratory, Strasbourg University Hospital | Sep 10, 2020 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Uncertain
T;T;T
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
.;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
H;H;.
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D
Sift4G
Pathogenic
D;D;.
Polyphen
D;D;.
Vest4
MutPred
Loss of MoRF binding (P = 0.0807);Loss of MoRF binding (P = 0.0807);Loss of MoRF binding (P = 0.0807);
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