Genetic Variant ZDHHC15:p.Ile285Val (chrX-75421874-T-C) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_144969.3(ZDHHC15):c.853A>G(p.Ile285Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000655 in 1,206,900 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 24 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000063 ( 0 hom., 2 hem., cov: 21)

Exomes 𝑓: 0.000066 ( 0 hom. 22 hem. )

Consequence

ZDHHC15
NM_144969.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.159

Publications

0 publications found

Variant links:

Genes affected

ZDHHC15 (HGNC:20342): (zinc finger DHHC-type palmitoyltransferase 15) The protein encoded by this gene belongs to the DHHC palmitoyltransferase family. Mutations in this gene are associated with mental retardatio X-linked type 91 (MRX91). Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2009]

ZDHHC15 Gene-Disease associations (from GenCC):

intellectual disability, X-linked 91
Inheritance: XL, Unknown Classification: LIMITED Submitted by: G2P, Labcorp Genetics (formerly Invitae)
X-linked complex neurodevelopmental disorder
Inheritance: XL Classification: NO_KNOWN Submitted by: ClinGen

ZDHHC15 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.031385273).

BS2

High Hemizygotes in GnomAd4 at 2 XL,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZDHHC15	NM_144969.3 link	c.853A>G	p.Ile285Val	missense_variant	Exon 9 of 12	ENST00000373367.8	NP_659406.1	Q96MV8-1B3KY34

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZDHHC15	ENST00000373367.8 link	c.853A>G	p.Ile285Val	missense_variant	Exon 9 of 12	1	NM_144969.3	ENSP00000362465.3		Q96MV8-1
ZDHHC15	ENST00000541184.1 link	c.826A>G	p.Ile276Val	missense_variant	Exon 8 of 11	2		ENSP00000445420.1		Q96MV8-3

Frequencies

GnomAD3 genomes

AF:

0.0000632

AC:

AN:

110737

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.000132

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000773

AC:

AN:

181064

AF XY:

0.0000608

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000173

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000657

AC:

AN:

1096163

Hom.:

Cov.:

AF XY:

0.0000608

AC XY:

AN XY:

361997

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26299

American (AMR)

AF:

0.00

AC:

AN:

35039

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19291

East Asian (EAS)

AF:

0.00

AC:

AN:

30143

South Asian (SAS)

AF:

0.00

AC:

AN:

53894

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40474

Middle Eastern (MID)

AF:

0.000486

AC:

AN:

4114

European-Non Finnish (NFE)

AF:

0.0000809

AC:

AN:

840918

Other (OTH)

AF:

0.0000435

AC:

AN:

45991

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000632

AC:

AN:

110737

Hom.:

Cov.:

AF XY:

0.0000607

AC XY:

AN XY:

32929

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30455

American (AMR)

AF:

0.00

AC:

AN:

10274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2641

East Asian (EAS)

AF:

0.00

AC:

AN:

3498

South Asian (SAS)

AF:

0.00

AC:

AN:

2604

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5944

Middle Eastern (MID)

AF:

0.00

AC:

AN:

238

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

52931

Other (OTH)

AF:

0.00

AC:

AN:

1474

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000130

Hom.:

Bravo

AF:

0.0000302

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.000107

AC:

EpiCase

AF:

0.000220

EpiControl

AF:

0.000419

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 03, 2022

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.853A>G (p.I285V) alteration is located in exon 9 (coding exon 9) of the ZDHHC15 gene. This alteration results from a A to G substitution at nucleotide position 853, causing the isoleucine (I) at amino acid position 285 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.050

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.92

CADD

Benign

0.21

(source)

DANN

Benign

0.42

DEOGEN2

Benign

0.094

T;.

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.75

T;T

M_CAP

Benign

0.0029

MetaRNN

Benign

0.031

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.38

N;.

PhyloP100

0.16

PrimateAI

Benign

0.31

PROVEAN

Benign

0.040

N;N

REVEL

Benign

0.029

Sift

Benign

0.93

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.033

B;.

Vest4

0.14

MVP

0.068

MPC

0.32

ClinPred

0.015

GERP RS

3.1

Varity_R

0.037

gMVP

0.39

Mutation Taster

=98/2

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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X-75421874-T-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over