X-129806437-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.1028C>T(p.Thr343Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: ZDHHC9 NM_016032.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.953

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=0.07204065).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZDHHC9	NM_016032.4	c.1028C>T	p.Thr343Ile	missense_variant	11/11	ENST00000357166.11
ZDHHC9	NM_001008222.3	c.1028C>T	p.Thr343Ile	missense_variant	10/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZDHHC9	ENST00000357166.11	c.1028C>T	p.Thr343Ile	missense_variant	11/11	1	NM_016032.4	P1
ZDHHC9	ENST00000371064.7	c.1028C>T	p.Thr343Ile	missense_variant	10/10	1		P1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Syndromic X-linked intellectual disability Raymond type Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 23, 2020

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 output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The isoleucine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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 conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces threonine with isoleucine at codon 343 of the ZDHHC9 protein (p.Thr343Ile). The threonine residue is moderately conserved and there is a moderate physicochemical difference between threonine and isoleucine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.82
Cadd	Benign	17
Dann	Benign	0.90
DEOGEN2	Benign	0.023	T;T
FATHMM_MKL	Benign	0.61	D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.072	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.33	N;N
REVEL	Benign	0.024
Sift	Benign	0.30	T;T
Sift4G	Benign	0.18	T;T
Polyphen		0.0	B;B
Vest4		0.10
MutPred		0.27		Loss of phosphorylation at T343 (P = 4e-04);Loss of phosphorylation at T343 (P = 4e-04);
MVP		0.043
MPC		1.2
ClinPred		0.058	T
GERP RS		1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.043
gMVP		0.20

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-128940413;