NM_016032.4:c.975C>T

Variant names:

• chrX-129810908-G-A
• rs139619000
• NM_016032.4:c.975C>T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_016032.4(ZDHHC9):​c.975C>T​(p.Ser325Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000749 in 1,207,269 control chromosomes in the GnomAD database, including 4 homozygotes. There are 234 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0040 (3 hom., 109 hem., cov: 22)
  • Exomes 𝑓: 0.00042 (1 hom. 125 hem.)
• Consequence: ZDHHC9 NM_016032.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.151
• 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: Benign. The variant received -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant X-129810908-G-A is Benign according to our data. Variant chrX-129810908-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 470205.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.151 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 3 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.975C>T	p.Ser325Ser	synonymous	Exon 10 of 11	NP_057116.2	Q9Y397
	ZDHHC9	NM_001008222.3		c.975C>T	p.Ser325Ser	synonymous	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.975C>T	p.Ser325Ser	synonymous	Exon 10 of 11	ENSP00000349689.6	Q9Y397
	ZDHHC9	ENST00000371064.7	TSL:1	c.975C>T	p.Ser325Ser	synonymous	Exon 9 of 10	ENSP00000360103.3	Q9Y397
	ZDHHC9	ENST00000860167.1		c.1065C>T	p.Ser355Ser	synonymous	Exon 11 of 12	ENSP00000530226.1

Frequencies

GnomAD3 genomes AF: 0.00396 AC: 441 AN: 111307 Hom.: 3 Cov.: 22

Gnomad AFR AF: 0.0127

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00430

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00418

Gnomad NFE AF: 0.0000566

Gnomad OTH AF: 0.00336

GnomAD2 exomes AF: 0.00130 AC: 238 AN: 183094 AF XY: 0.000814

Gnomad AFR exome AF: 0.0139

Gnomad AMR exome AF: 0.00161

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000978

Gnomad OTH exome AF: 0.000885

GnomAD4 exome AF: 0.000422 AC: 463 AN: 1095909 Hom.: 1 Cov.: 30 AF XY: 0.000346 AC XY: 125 AN XY: 361355

African (AFR) AF: 0.0117 AC: 309 AN: 26353

American (AMR) AF: 0.00182 AC: 64 AN: 35193

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19374

East Asian (EAS) AF: 0.00 AC: 0 AN: 30194

South Asian (SAS) AF: 0.0000925 AC: 5 AN: 54047

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40521

Middle Eastern (MID) AF: 0.000732 AC: 3 AN: 4101

European-Non Finnish (NFE) AF: 0.0000190 AC: 16 AN: 840102

Other (OTH) AF: 0.00143 AC: 66 AN: 46024

GnomAD4 genome AF: 0.00396 AC: 441 AN: 111360 Hom.: 3 Cov.: 22 AF XY: 0.00325 AC XY: 109 AN XY: 33568

African (AFR) AF: 0.0126 AC: 387 AN: 30608

American (AMR) AF: 0.00429 AC: 45 AN: 10488

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2630

East Asian (EAS) AF: 0.00 AC: 0 AN: 3567

South Asian (SAS) AF: 0.00 AC: 0 AN: 2634

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6029

Middle Eastern (MID) AF: 0.00459 AC: 1 AN: 218

European-Non Finnish (NFE) AF: 0.0000566 AC: 3 AN: 53005

Other (OTH) AF: 0.00332 AC: 5 AN: 1505

Alfa AF: 0.00204 Hom.: 11

Bravo AF: 0.00520

EpiCase AF: 0.0000545

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	History of neurodevelopmental disorder (1)
-	-	1	not provided (1)
-	-	1	not specified (1)
-	-	1	Syndromic X-linked intellectual disability Raymond type (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	4.5
DANN	Benign	0.44
PhyloP100		0.15
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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: rs139619000; hg19: chrX-128944884;