rs753387074

Variant names:

• chrX-129810954-C-A
• rs753387074
• NM_016032.4:c.929G>T

Your query was ambiguous. Multiple possible variants found:

• chrX-129810954-C-A
• chrX-129810954-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_016032.4(ZDHHC9):​c.929G>T​(p.Arg310Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000911 in 1,097,974 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. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R310Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: ZDHHC9 NM_016032.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.00
• Publications: 0 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: G2P, Labcorp Genetics (formerly Invitae), ClinGen
• X-linked intellectual disability with marfanoid habitus

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21569994).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZDHHC9	NM_016032.4	c.929G>T	p.Arg310Leu	missense_variant	Exon 10 of 11	ENST00000357166.11	NP_057116.2
ZDHHC9	NM_001008222.3	c.929G>T	p.Arg310Leu	missense_variant	Exon 9 of 10		NP_001008223.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZDHHC9	ENST00000357166.11	c.929G>T	p.Arg310Leu	missense_variant	Exon 10 of 11	1	NM_016032.4	ENSP00000349689.6
ZDHHC9	ENST00000371064.7	c.929G>T	p.Arg310Leu	missense_variant	Exon 9 of 10	1		ENSP00000360103.3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1097974 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 363332

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 26399

American (AMR) AF: 0.00 AC: 0 AN: 35198

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19382

East Asian (EAS) AF: 0.0000331 AC: 1 AN: 30204

South Asian (SAS) AF: 0.00 AC: 0 AN: 54099

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40527

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4110

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 841970

Other (OTH) AF: 0.00 AC: 0 AN: 46085

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.030	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.024	T;T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.79	.;T
M_CAP	Benign	0.0075	T
MetaRNN	Benign	0.22	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.84	L;L
PhyloP100		4.0
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.30	N;N
REVEL	Benign	0.12
Sift	Benign	0.23	T;T
Sift4G	Benign	0.35	T;T
Polyphen		0.0030	B;B
Vest4		0.49
MutPred		0.22		Gain of glycosylation at T314 (P = 0.1035);Gain of glycosylation at T314 (P = 0.1035);
MVP		0.77
MPC		1.3
ClinPred		0.55	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.20
gMVP		0.43
Mutation Taster		=73/27	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs753387074; hg19: chrX-128944930;