rs606231183

Positions:

• chrX-129841774-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_016032.4(ZDHHC9):​c.167+5G>C variant causes a splice donor 5th base, intron 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. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 23)
• Consequence: ZDHHC9 NM_016032.4 splice_donor_5th_base, intron
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.91

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant X-129841774-C-G is Pathogenic according to our data. Variant chrX-129841774-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 10710.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZDHHC9	NM_016032.4	c.167+5G>C		splice_donor_5th_base_variant, intron_variant		ENST00000357166.11	NP_057116.2
ZDHHC9	NM_001008222.3	c.167+5G>C		splice_donor_5th_base_variant, intron_variant			NP_001008223.1
ZDHHC9	XM_011531348.4	c.167+5G>C		splice_donor_5th_base_variant, intron_variant			XP_011529650.1
ZDHHC9	XM_047442151.1	c.167+5G>C		splice_donor_5th_base_variant, intron_variant			XP_047298107.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZDHHC9	ENST00000357166.11	c.167+5G>C		splice_donor_5th_base_variant, intron_variant		1	NM_016032.4	ENSP00000349689	P1
ZDHHC9	ENST00000371064.7	c.167+5G>C		splice_donor_5th_base_variant, intron_variant		1		ENSP00000360103	P1
ZDHHC9	ENST00000406492.2	c.167+5G>C		splice_donor_5th_base_variant, intron_variant		5		ENSP00000383991
ZDHHC9	ENST00000433917.5	c.46+5G>C		splice_donor_5th_base_variant, intron_variant		3		ENSP00000406165

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Syndromic X-linked intellectual disability Raymond type Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 2009

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.25
CADD	Benign	20
DANN	Benign	0.97
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.95		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.95		Position offset: 5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs606231183; hg19: chrX-128975750;