Genetic Variant ZDHHC15:p.Arg208Leu (chrX-75424765-C-A) – 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_144969.3(ZDHHC15):c.623G>T(p.Arg208Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000922 in 1,084,727 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R208H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 9.2e-7 ( 0 hom. 1 hem. )

Consequence

ZDHHC15
NM_144969.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.19

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:

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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;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZDHHC15	NM_144969.3 link	c.623G>T	p.Arg208Leu	missense_variant	Exon 8 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.623G>T	p.Arg208Leu	missense_variant	Exon 8 of 12	1	NM_144969.3	ENSP00000362465.3		Q96MV8-1
ZDHHC15	ENST00000541184.1 link	c.596G>T	p.Arg199Leu	missense_variant	Exon 7 of 11	2		ENSP00000445420.1		Q96MV8-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

9.22e-7

AC:

AN:

1084727

Hom.:

Cov.:

AF XY:

0.00000284

AC XY:

AN XY:

352239

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25791

American (AMR)

AF:

0.00

AC:

AN:

33543

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18991

East Asian (EAS)

AF:

0.00

AC:

AN:

29553

South Asian (SAS)

AF:

0.00

AC:

AN:

50915

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40169

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4081

European-Non Finnish (NFE)

AF:

0.00000120

AC:

AN:

836147

Other (OTH)

AF:

0.00

AC:

AN:

45537

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 17, 2017

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.28

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.50

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.21

T;.

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.90

D;D

M_CAP

Uncertain

0.20

MetaRNN

Uncertain

0.52

D;D

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.3

L;.

PhyloP100

1.2

PrimateAI

Uncertain

0.55

PROVEAN

Uncertain

-2.9

D;D

REVEL

Benign

0.16

Sift

Benign

0.13

T;T

Sift4G

Benign

0.33

T;T

Polyphen

0.95

P;.

Vest4

0.56

MutPred

0.59

Loss of methylation at R208 (P = 0.0395);.;

MVP

0.18

MPC

0.48

ClinPred

0.95

GERP RS

5.6

Varity_R

0.33

gMVP

0.74

Mutation Taster

=84/16

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.23

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.23

Position offset: 19

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

Publications

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X-75424765-C-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over