Genetic Variant ZDHHC15:p.Ala149Ser (chrX-75431455-C-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.445G>T(p.Ala149Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000489 in 1,205,983 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 9 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00029 ( 0 hom., 4 hem., cov: 22)

Exomes 𝑓: 0.000025 ( 0 hom. 5 hem. )

Consequence

ZDHHC15
NM_144969.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.62

Publications

1 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=0.050448745).

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.445G>T	p.Ala149Ser	missense_variant	Exon 5 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.445G>T	p.Ala149Ser	missense_variant	Exon 5 of 12	1	NM_144969.3	ENSP00000362465.3		Q96MV8-1
ZDHHC15	ENST00000541184.1 link	c.418G>T	p.Ala140Ser	missense_variant	Exon 4 of 11	2		ENSP00000445420.1		Q96MV8-3

Frequencies

GnomAD3 genomes

AF:

0.000289

AC:

AN:

110625

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00105

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

GnomAD2 exomes

AF:

0.0000555

AC:

AN:

180317

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.000769

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000246

AC:

AN:

1095358

Hom.:

Cov.:

AF XY:

0.0000139

AC XY:

AN XY:

360940

show subpopulations

African (AFR)

AF:

0.000911

AC:

AN:

26353

American (AMR)

AF:

0.00

AC:

AN:

35051

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19302

East Asian (EAS)

AF:

0.00

AC:

AN:

30150

South Asian (SAS)

AF:

0.00

AC:

AN:

53474

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40402

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4117

European-Non Finnish (NFE)

AF:

0.00000238

AC:

AN:

840553

Other (OTH)

AF:

0.0000218

AC:

AN:

45956

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000289

AC:

AN:

110625

Hom.:

Cov.:

AF XY:

0.000122

AC XY:

AN XY:

32855

show subpopulations

African (AFR)

AF:

0.00105

AC:

AN:

30405

American (AMR)

AF:

0.00

AC:

AN:

10270

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2643

East Asian (EAS)

AF:

0.00

AC:

AN:

3513

South Asian (SAS)

AF:

0.00

AC:

AN:

2560

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5827

Middle Eastern (MID)

AF:

0.00

AC:

AN:

233

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53010

Other (OTH)

AF:

0.00

AC:

AN:

1480

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000108

Hom.:

Bravo

AF:

0.000264

ESP6500AA

AF:

0.00130

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 21, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.445G>T (p.A149S) alteration is located in exon 5 (coding exon 5) of the ZDHHC15 gene. This alteration results from a G to T substitution at nucleotide position 445, causing the alanine (A) at amino acid position 149 to be replaced by a serine (S). 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

0.068

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.72

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.071

T;.

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.84

T;T

M_CAP

Uncertain

0.18

MetaRNN

Benign

0.050

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.46

N;.

PhyloP100

4.6

PrimateAI

Uncertain

0.60

PROVEAN

Benign

0.71

N;N

REVEL

Benign

0.031

Sift

Benign

0.49

T;T

Sift4G

Benign

0.71

T;T

Polyphen

0.011

B;.

Vest4

0.22

MVP

0.082

MPC

0.35

ClinPred

0.065

GERP RS

4.4

Varity_R

0.20

gMVP

0.45

Mutation Taster

=97/3

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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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X-75431455-C-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