NM_016032.4:c.448C>T

Variant names:

• chrX-129823718-G-A
• rs137852215
• NM_016032.4:c.448C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_016032.4(ZDHHC9):​c.448C>T​(p.Pro150Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,098,199 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. 14/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: ZDHHC9 NM_016032.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.60
• Publications: 11 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_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.965
• PP5: Variant X-129823718-G-A is Pathogenic according to our data. Variant chrX-129823718-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 10712.Status of the report is no_assertion_criteria_provided, 0 stars.

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.448C>T	p.Pro150Ser	missense	Exon 5 of 11	NP_057116.2	Q9Y397
	ZDHHC9	NM_001008222.3		c.448C>T	p.Pro150Ser	missense	Exon 4 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.448C>T	p.Pro150Ser	missense	Exon 5 of 11	ENSP00000349689.6	Q9Y397
	ZDHHC9	ENST00000371064.7	TSL:1	c.448C>T	p.Pro150Ser	missense	Exon 4 of 10	ENSP00000360103.3	Q9Y397
	ZDHHC9	ENST00000860167.1		c.448C>T	p.Pro150Ser	missense	Exon 5 of 12	ENSP00000530226.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1098199 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 363553

African (AFR) AF: 0.00 AC: 0 AN: 26402

American (AMR) AF: 0.00 AC: 0 AN: 35207

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19386

East Asian (EAS) AF: 0.00 AC: 0 AN: 30206

South Asian (SAS) AF: 0.00 AC: 0 AN: 54149

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40500

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4136

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 842116

Other (OTH) AF: 0.00 AC: 0 AN: 46097

GnomAD4 genome Cov.: 24

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Syndromic X-linked intellectual disability Raymond type (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.24	T
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.96	D
MetaSVM	Benign	-0.46	T
MutationAssessor	Pathogenic	3.4	M
PhyloP100		9.6
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-7.8	D
REVEL	Pathogenic	0.73
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0020	D
Polyphen		1.0	D
Vest4		0.91
MutPred		0.85		Gain of catalytic residue at P150 (P = 0.0722)
MVP		0.82
MPC		2.2
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.98
gMVP		0.96
Mutation Taster		=16/84	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs137852215; hg19: chrX-128957694; COSMIC: COSV64097494;