Genetic Variant ZDHHC9:p.Pro338Arg (chrX-129806452-G-C) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_016032.4(ZDHHC9):c.1013C>G(p.Pro338Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000165 in 1,209,380 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P338L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000090 ( 0 hom., 1 hem., cov: 22)

Exomes 𝑓: 9.1e-7 ( 0 hom. 0 hem. )

Consequence

ZDHHC9
NM_016032.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.89

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.28573984).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZDHHC9	NM_016032.4 link	c.1013C>G	p.Pro338Arg	missense_variant	Exon 11 of 11	ENST00000357166.11	NP_057116.2	Q9Y397
ZDHHC9	NM_001008222.3 link	c.1013C>G	p.Pro338Arg	missense_variant	Exon 10 of 10		NP_001008223.1	Q9Y397

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZDHHC9	ENST00000357166.11 link	c.1013C>G	p.Pro338Arg	missense_variant	Exon 11 of 11	1	NM_016032.4	ENSP00000349689.6		Q9Y397
ZDHHC9	ENST00000371064.7 link	c.1013C>G	p.Pro338Arg	missense_variant	Exon 10 of 10	1		ENSP00000360103.3		Q9Y397

Frequencies

GnomAD3 genomes

AF:

0.00000898

AC:

AN:

111410

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000327

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

9.11e-7

AC:

AN:

1097970

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

363330

show subpopulations

African (AFR)

AF:

0.0000379

AC:

AN:

26397

American (AMR)

AF:

0.00

AC:

AN:

35204

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19385

East Asian (EAS)

AF:

0.00

AC:

AN:

30203

South Asian (SAS)

AF:

0.00

AC:

AN:

54138

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40527

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4102

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

841929

Other (OTH)

AF:

0.00

AC:

AN:

46085

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000898

AC:

AN:

111410

Hom.:

Cov.:

AF XY:

0.0000298

AC XY:

AN XY:

33590

show subpopulations

African (AFR)

AF:

0.0000327

AC:

AN:

30547

American (AMR)

AF:

0.00

AC:

AN:

10445

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2647

East Asian (EAS)

AF:

0.00

AC:

AN:

3554

South Asian (SAS)

AF:

0.00

AC:

AN:

2658

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6028

Middle Eastern (MID)

AF:

0.00

AC:

AN:

237

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53113

Other (OTH)

AF:

0.00

AC:

AN:

1498

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.045

T;T

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.74

.;T

M_CAP

Pathogenic

0.43

MetaRNN

Benign

0.29

T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.2

L;L

PhyloP100

3.9

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-1.1

N;N

REVEL

Benign

0.19

Sift

Benign

0.038

D;D

Sift4G

Benign

0.21

T;T

Polyphen

1.0

D;D

Vest4

0.30

MutPred

0.18

Loss of glycosylation at S334 (P = 0.1579);Loss of glycosylation at S334 (P = 0.1579);

MVP

0.26

MPC

1.1

ClinPred

0.61

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.20

gMVP

0.46

Mutation Taster

=81/19

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over