X-129806464-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_016032.4(ZDHHC9):c.1001C>T(p.Ser334Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000179 in 111,544 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: 𝑓 0.000018 (0 hom., 0 hem., cov: 22)
• Consequence: ZDHHC9 NM_016032.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.62

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09343779).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZDHHC9	NM_016032.4	c.1001C>T	p.Ser334Leu	missense_variant	11/11	ENST00000357166.11
ZDHHC9	NM_001008222.3	c.1001C>T	p.Ser334Leu	missense_variant	10/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZDHHC9	ENST00000357166.11	c.1001C>T	p.Ser334Leu	missense_variant	11/11	1	NM_016032.4	P1
ZDHHC9	ENST00000371064.7	c.1001C>T	p.Ser334Leu	missense_variant	10/10	1		P1

Frequencies

GnomAD3 genomes AF: 0.0000179 AC: 2 AN: 111544 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 33712

Gnomad AFR AF: 0.0000654

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: 0.00000545 AC: 1 AN: 183324 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 67788

Gnomad AFR exome AF: 0.0000760

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.0000179 AC: 2 AN: 111544 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 33712

Gnomad4 AFR AF: 0.0000654

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: 0.00000756

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Syndromic X-linked intellectual disability Raymond type Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jun 12, 2018	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with ZDHHC9-related disease. This variant is present in population databases (rs748573163, ExAC 0.01%). This sequence change replaces serine with leucine at codon 334 of the ZDHHC9 protein (p.Ser334Leu). The serine residue is moderately conserved and there is a large physicochemical difference between serine and leucine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.61
Cadd	Benign	20
Dann	Uncertain	0.99
DEOGEN2	Benign	0.058	T;T
FATHMM_MKL	Benign	0.69	D
M_CAP	Pathogenic	0.38	D
MetaRNN	Benign	0.093	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.1	N;N
REVEL	Benign	0.047
Sift	Benign	0.048	D;D
Sift4G	Benign	0.25	T;T
Polyphen		0.069	B;B
Vest4		0.098
MutPred		0.22		Loss of phosphorylation at S334 (P = 0.0171);Loss of phosphorylation at S334 (P = 0.0171);
MVP		0.13
MPC		0.97
ClinPred		0.068	T
GERP RS		5.5
Varity_R		0.11
gMVP		0.23

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: rs748573163; hg19: chrX-128940440;