Genetic Variant ZDHHC9:p.Asp259Glu (chrX-129812718-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_016032.4(ZDHHC9):c.777C>A(p.Asp259Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. D259D) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 23)

Consequence

ZDHHC9
NM_016032.4 missense, splice_region

Scores

Splicing: ADA: 0.00003889

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.38

Publications

0 publications found

Variant links:

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: G2P, Labcorp Genetics (formerly Invitae), ClinGen
X-linked intellectual disability with marfanoid habitus
Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ZDHHC9 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZDHHC9	NM_016032.4	MANE Select	c.777C>A	p.Asp259Glu	missense splice_region	Exon 8 of 11	NP_057116.2
	ZDHHC9	NM_001008222.3		c.777C>A	p.Asp259Glu	missense splice_region	Exon 7 of 10	NP_001008223.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ZDHHC9	ENST00000357166.11	TSL:1 MANE Select	c.777C>A	p.Asp259Glu	missense splice_region	Exon 8 of 11	ENSP00000349689.6
ZDHHC9	ENST00000371064.7	TSL:1	c.777C>A	p.Asp259Glu	missense splice_region	Exon 7 of 10	ENSP00000360103.3
ZDHHC9	ENST00000433917.5	TSL:3	c.516C>A	p.Asp172Glu	missense splice_region	Exon 5 of 6	ENSP00000406165.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Benign

-0.073

BayesDel_noAF

Benign

-0.34

CADD

Benign

5.8

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.14

FATHMM_MKL

Benign

0.098

LIST_S2

Uncertain

0.89

M_CAP

Benign

0.016

MetaRNN

Uncertain

0.71

MetaSVM

Uncertain

-0.18

MutationAssessor

Uncertain

2.5

PhyloP100

-2.4

PrimateAI

Pathogenic

0.89

PROVEAN

Uncertain

-3.9

REVEL

Uncertain

0.33

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0040

Polyphen

0.95

Vest4

0.83

MutPred

0.28

Gain of disorder (P = 0.0966)

MVP

0.55

MPC

1.8

ClinPred

0.99

GERP RS

-9.1

Varity_R

0.91

gMVP

0.91

Mutation Taster

=59/41

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000039

dbscSNV1_RF

Benign

0.12

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over