rs137852214

chrX-129823724-G-A

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PP3_Strong PP5_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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R148Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 24)
• Consequence: ZDHHC9 NM_016032.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• 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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 98) in uniprot entity ZDHC9_HUMAN there are 5 pathogenic changes around while only 2 benign (71%) in NM_016032.4
• 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	UniProt
ZDHHC9	NM_016032.4	c.442C>T	p.Arg148Trp	missense_variant	5/11	ENST00000357166.11
ZDHHC9	NM_001008222.3	c.442C>T	p.Arg148Trp	missense_variant	4/10
ZDHHC9	XM_047442151.1	c.442C>T	p.Arg148Trp	missense_variant	5/8
ZDHHC9	XM_011531348.4	c.442C>T	p.Arg148Trp	missense_variant	5/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZDHHC9	ENST00000357166.11	c.442C>T	p.Arg148Trp	missense_variant	5/11	1	NM_016032.4	P1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Syndromic X-linked intellectual disability Raymond type Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	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	- -
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. -

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
Cadd	Pathogenic	33
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.43	T;T;T
FATHMM_MKL	Uncertain	0.88	D
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Uncertain	0.098	D
MutationAssessor	Pathogenic	4.9	H;H;.
MutationTaster	Benign	1.0	A;A
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-7.8	D;D;D
REVEL	Pathogenic	0.67
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0010	D;D;.
Polyphen		1.0	D;D;.
Vest4		0.71
MutPred		0.94		Loss of MoRF binding (P = 0.0807);Loss of MoRF binding (P = 0.0807);Loss of MoRF binding (P = 0.0807);
MVP		0.96
MPC		2.3
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.99
gMVP		0.99

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

Other links and lift over

dbSNP: rs137852214; hg19: chrX-128957700; COSMIC: COSV64097253;