rs1556006445

Variant names:

• chrX-129823769-T-G
• rs1556006445
• NM_016032.4:c.397A>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_016032.4(ZDHHC9):​c.397A>C​(p.Asn133His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 24)
• Consequence: ZDHHC9 NM_016032.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.67

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.41404128).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZDHHC9	NM_016032.4	c.397A>C	p.Asn133His	missense_variant	Exon 5 of 11	ENST00000357166.11	NP_057116.2
ZDHHC9	NM_001008222.3	c.397A>C	p.Asn133His	missense_variant	Exon 4 of 10		NP_001008223.1
ZDHHC9	XM_047442151.1	c.397A>C	p.Asn133His	missense_variant	Exon 5 of 8		XP_047298107.1
ZDHHC9	XM_011531348.4	c.397A>C	p.Asn133His	missense_variant	Exon 5 of 6		XP_011529650.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZDHHC9	ENST00000357166.11	c.397A>C	p.Asn133His	missense_variant	Exon 5 of 11	1	NM_016032.4	ENSP00000349689.6

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 24

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

Jan 16, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a ZDHHC9-related disease. This sequence change replaces asparagine with histidine at codon 133 of the ZDHHC9 protein (p.Asn133His). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and histidine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.40
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T;T;T
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.88	.;D;D
M_CAP	Pathogenic	0.30	D
MetaRNN	Benign	0.41	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	L;L;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-2.2	N;N;N
REVEL	Uncertain	0.34
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.0060	D;D;.
Polyphen		0.99	D;D;.
Vest4		0.38
MutPred		0.57		Loss of MoRF binding (P = 0.1241);Loss of MoRF binding (P = 0.1241);Loss of MoRF binding (P = 0.1241);
MVP		0.24
MPC		2.2
ClinPred		0.87	D
GERP RS		5.7
Varity_R		0.66
gMVP		0.79

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: rs1556006445; hg19: chrX-128957745;