rs751918374

chrX-129812718-G-AchrX-129812718-G-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_016032.4(ZDHHC9):c.777C>T(p.Asp259=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000267 in 1,198,491 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 7 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., 2 hem., cov: 23)
  • Exomes 𝑓: 0.000028 (0 hom. 5 hem.)
• Consequence: ZDHHC9 NM_016032.4 splice_region, synonymous
• Scores: Splicing: ADA: 0.0005012
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.38

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 Benign. Variant got -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant X-129812718-G-A is Benign according to our data. Variant chrX-129812718-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 470202.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-2.38 with no splicing effect.
• BS2: High Hemizygotes in GnomAd at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZDHHC9	NM_016032.4	c.777C>T	p.Asp259=	splice_region_variant, synonymous_variant	8/11	ENST00000357166.11
ZDHHC9	NM_001008222.3	c.777C>T	p.Asp259=	splice_region_variant, synonymous_variant	7/10
ZDHHC9	XM_047442151.1	c.*179C>T		3_prime_UTR_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZDHHC9	ENST00000357166.11	c.777C>T	p.Asp259=	splice_region_variant, synonymous_variant	8/11	1	NM_016032.4	P1
ZDHHC9	ENST00000371064.7	c.777C>T	p.Asp259=	splice_region_variant, synonymous_variant	7/10	1		P1
ZDHHC9	ENST00000433917.5	c.519C>T	p.Asp173=	splice_region_variant, synonymous_variant	5/6	3

Frequencies

GnomAD3 genomes AF: 0.0000179 AC: 2 AN: 112017 Hom.: 0 Cov.: 23 AF XY: 0.0000585 AC XY: 2 AN XY: 34177

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000949

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: 0.0000188

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000600 AC: 11 AN: 183204 Hom.: 0 AF XY: 0.0000296 AC XY: 2 AN XY: 67650

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000328

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000721

Gnomad SAS 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: 0.0000276 AC: 30 AN: 1086474 Hom.: 0 Cov.: 29 AF XY: 0.0000142 AC XY: 5 AN XY: 353122

Gnomad4 AFR exome AF: 0.0000382

Gnomad4 AMR exome AF: 0.000284

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000664

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000180

Gnomad4 OTH exome AF: 0.0000438

GnomAD4 genome AF: 0.0000179 AC: 2 AN: 112017 Hom.: 0 Cov.: 23 AF XY: 0.0000585 AC XY: 2 AN XY: 34177

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000949

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000188

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000378

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Syndromic X-linked intellectual disability Raymond type Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 15, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	0.035
Dann	Benign	0.59

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00050
dbscSNV1_RF	Benign	0.014
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

Publications

LitVar

Other links and lift over

dbSNP: rs751918374; hg19: chrX-128946694;