rs753387074

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_016032.4(ZDHHC9):​c.929G>A​(p.Arg310Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000356 in 1,209,294 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 14 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., 2 hem., cov: 22)
  • Exomes 𝑓: 0.000036 (0 hom. 12 hem.)
• Consequence: ZDHHC9 NM_016032.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• 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: Labcorp Genetics (formerly Invitae), G2P, ClinGen
• X-linked intellectual disability with marfanoid habitus

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0873273).
• BS2: High Hemizygotes in GnomAd4 at 2 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016032.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZDHHC9	NM_016032.4	MANE Select	c.929G>A	p.Arg310Gln	missense	Exon 10 of 11	NP_057116.2	Q9Y397
	ZDHHC9	NM_001008222.3		c.929G>A	p.Arg310Gln	missense	Exon 9 of 10	NP_001008223.1	Q9Y397

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZDHHC9	ENST00000357166.11	TSL:1 MANE Select	c.929G>A	p.Arg310Gln	missense	Exon 10 of 11	ENSP00000349689.6	Q9Y397
	ZDHHC9	ENST00000371064.7	TSL:1	c.929G>A	p.Arg310Gln	missense	Exon 9 of 10	ENSP00000360103.3	Q9Y397
	ZDHHC9	ENST00000860167.1		c.1019G>A	p.Arg340Gln	missense	Exon 11 of 12	ENSP00000530226.1

Frequencies

GnomAD3 genomes AF: 0.0000269 AC: 3 AN: 111320 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000286

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

GnomAD2 exomes AF: 0.0000164 AC: 3 AN: 183235 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000730

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000122

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000364 AC: 40 AN: 1097974 Hom.: 0 Cov.: 30 AF XY: 0.0000330 AC XY: 12 AN XY: 363332

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

American (AMR) AF: 0.0000284 AC: 1 AN: 35198

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

East Asian (EAS) AF: 0.00 AC: 0 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: 0.0000463 AC: 39 AN: 841970

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

GnomAD4 genome AF: 0.0000269 AC: 3 AN: 111320 Hom.: 0 Cov.: 22 AF XY: 0.0000597 AC XY: 2 AN XY: 33514

African (AFR) AF: 0.00 AC: 0 AN: 30558

American (AMR) AF: 0.000286 AC: 3 AN: 10482

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2631

East Asian (EAS) AF: 0.00 AC: 0 AN: 3568

South Asian (SAS) AF: 0.00 AC: 0 AN: 2633

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6002

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53032

Other (OTH) AF: 0.00 AC: 0 AN: 1493

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000491

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	Intellectual disability (1)
-	1	-	not provided (1)
-	1	-	Syndromic X-linked intellectual disability Raymond type (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.021	T
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.0070	T
MetaRNN	Benign	0.087	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.58	N
PhyloP100		4.0
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	0.63	N
REVEL	Benign	0.058
Sift	Benign	0.32	T
Sift4G	Benign	0.64	T
Polyphen		0.14	B
Vest4		0.23
MutPred		0.19		Loss of catalytic residue at R310 (P = 0.098)
MVP		0.42
MPC		1.2
ClinPred		0.14	T
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.16
gMVP		0.35
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs753387074; hg19: chrX-128944930;