Genetic Variant ZDHHC15:p.Thr335Met (chrX-75379162-G-A) – 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.1004C>T(p.Thr335Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000819 in 1,209,498 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 25 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 0.00018 ( 0 hom., 4 hem., cov: 23)

Exomes 𝑓: 0.000072 ( 0 hom. 21 hem. )

Consequence

ZDHHC15
NM_144969.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.79

Publications

4 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=0.023301125).

BS2

High Hemizygotes in GnomAd4 at 4 XL,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZDHHC15	NM_144969.3 link	c.1004C>T	p.Thr335Met	missense_variant	Exon 11 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.1004C>T	p.Thr335Met	missense_variant	Exon 11 of 12	1	NM_144969.3	ENSP00000362465.3		Q96MV8-1
ZDHHC15	ENST00000541184.1 link	c.977C>T	p.Thr326Met	missense_variant	Exon 10 of 11	2		ENSP00000445420.1		Q96MV8-3

Frequencies

GnomAD3 genomes

AF:

0.000179

AC:

AN:

111822

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000455

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000190

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000375

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000564

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000126

AC:

AN:

183017

AF XY:

0.0000444

show subpopulations

Gnomad AFR exome

AF:

0.000608

Gnomad AMR exome

AF:

0.000183

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000722

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000110

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000720

AC:

AN:

1097623

Hom.:

Cov.:

AF XY:

0.0000578

AC XY:

AN XY:

363073

show subpopulations

African (AFR)

AF:

0.000720

AC:

AN:

26387

American (AMR)

AF:

0.000199

AC:

AN:

35185

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19367

East Asian (EAS)

AF:

0.0000994

AC:

AN:

30185

South Asian (SAS)

AF:

0.0000554

AC:

AN:

54113

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40512

Middle Eastern (MID)

AF:

0.000484

AC:

AN:

4134

European-Non Finnish (NFE)

AF:

0.0000475

AC:

AN:

841675

Other (OTH)

AF:

0.000109

AC:

AN:

46065

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000179

AC:

AN:

111875

Hom.:

Cov.:

AF XY:

0.000117

AC XY:

AN XY:

34061

show subpopulations

African (AFR)

AF:

0.000454

AC:

AN:

30852

American (AMR)

AF:

0.000190

AC:

AN:

10517

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2645

East Asian (EAS)

AF:

0.00

AC:

AN:

3552

South Asian (SAS)

AF:

0.000377

AC:

AN:

2655

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6067

Middle Eastern (MID)

AF:

0.00

AC:

AN:

215

European-Non Finnish (NFE)

AF:

0.0000564

AC:

AN:

53159

Other (OTH)

AF:

0.00

AC:

AN:

1526

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.522

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000969

Hom.:

Bravo

AF:

0.000185

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.000782

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.0000824

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 27, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1004C>T (p.T335M) alteration is located in exon 11 (coding exon 11) of the ZDHHC15 gene. This alteration results from a C to T substitution at nucleotide position 1004, causing the threonine (T) at amino acid position 335 to be replaced by a methionine (M). 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

0.081

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.83

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.083

T;.

FATHMM_MKL

Benign

0.43

LIST_S2

Benign

0.72

T;T

M_CAP

Benign

0.0076

MetaRNN

Benign

0.023

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-1.5

N;.

PhyloP100

1.8

PrimateAI

Benign

0.44

PROVEAN

Benign

0.26

N;N

REVEL

Benign

0.041

Sift

Benign

0.076

T;T

Sift4G

Benign

0.14

T;T

Polyphen

0.0010

B;.

Vest4

0.26

MVP

0.043

MPC

0.39

ClinPred

0.019

GERP RS

2.9

Varity_R

0.024

gMVP

0.29

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.13

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

X-75379162-G-A

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