X-129812718-G-T

Variant summary

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

The NM_016032.4(ZDHHC9):c.777C>A(p.Asp259Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. D259D) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 23)
• Consequence: ZDHHC9 NM_016032.4 missense, splice_region
• Scores: Splicing: ADA: 0.00003889
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.38

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZDHHC9	NM_016032.4	c.777C>A	p.Asp259Glu	missense_variant, splice_region_variant	8/11	ENST00000357166.11
ZDHHC9	NM_001008222.3	c.777C>A	p.Asp259Glu	missense_variant, splice_region_variant	7/10
ZDHHC9	XM_047442151.1	c.*179C>A		3_prime_UTR_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZDHHC9	ENST00000357166.11	c.777C>A	p.Asp259Glu	missense_variant, splice_region_variant	8/11	1	NM_016032.4	P1
ZDHHC9	ENST00000371064.7	c.777C>A	p.Asp259Glu	missense_variant, splice_region_variant	7/10	1		P1
ZDHHC9	ENST00000433917.5	c.519C>A	p.Asp173Glu	missense_variant, splice_region_variant	5/6	3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Benign	-0.073	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	5.8
Dann	Uncertain	0.99
DEOGEN2	Benign	0.14	T;T
FATHMM_MKL	Benign	0.098	N
M_CAP	Benign	0.016	T
MetaRNN	Uncertain	0.71	D;D
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Uncertain	2.5	M;M
MutationTaster	Benign	0.57	D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-3.9	D;D
REVEL	Uncertain	0.33
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.0040	D;D
Polyphen		0.95	P;P
Vest4		0.83
MutPred		0.28		Gain of disorder (P = 0.0966);Gain of disorder (P = 0.0966);
MVP		0.55
MPC		1.8
ClinPred		0.99	D
GERP RS		-9.1
Varity_R		0.91
gMVP		0.91

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000039
dbscSNV1_RF	Benign	0.12
SpliceAI score (max)		0.010		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: rs751918374; hg19: chrX-128946694;