rs137852214

Variant names:

• chrX-129823724-G-A
• rs137852214
• NM_016032.4:c.442C>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PS3 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. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV001587967: Experimental studies have shown that this missense change affects ZDHHC9 function (PMID:24811172).". 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:6
• Conservation: PhyloP100: 6.11
• Publications: 7 publications found

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]

ZDHHC9 Gene-Disease associations (from GenCC):

• syndromic X-linked intellectual disability Raymond type

  Inheritance: XL Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen
• X-linked intellectual disability with marfanoid habitus

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV001587967: Experimental studies have shown that this missense change affects ZDHHC9 function (PMID: 24811172).
• 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 Pathogenic/Likely_pathogenic. ClinVar VariationId is 10711.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016032.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZDHHC9	NM_016032.4	MANE Select	c.442C>T	p.Arg148Trp	missense	Exon 5 of 11	NP_057116.2	Q9Y397
	ZDHHC9	NM_001008222.3		c.442C>T	p.Arg148Trp	missense	Exon 4 of 10	NP_001008223.1	Q9Y397

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZDHHC9	ENST00000357166.11	TSL:1 MANE Select	c.442C>T	p.Arg148Trp	missense	Exon 5 of 11	ENSP00000349689.6	Q9Y397
	ZDHHC9	ENST00000371064.7	TSL:1	c.442C>T	p.Arg148Trp	missense	Exon 4 of 10	ENSP00000360103.3	Q9Y397
	ZDHHC9	ENST00000860167.1		c.442C>T	p.Arg148Trp	missense	Exon 5 of 12	ENSP00000530226.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 24

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Syndromic X-linked intellectual disability Raymond type (4)
1	-	-	Intellectual disability (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.098	D
MutationAssessor	Pathogenic	4.9	H
PhyloP100		6.1
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-7.8	D
REVEL	Pathogenic	0.67
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.71
MutPred		0.94		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
Mutation Taster		=3/97	disease causing (ClinVar)

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

Other links and lift over

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