X-75379162-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

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. 14/20 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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.79

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.023301125).
• BS2: High Hemizygotes in GnomAd at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZDHHC15	NM_144969.3	c.1004C>T	p.Thr335Met	missense_variant	11/12	ENST00000373367.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZDHHC15	ENST00000373367.8	c.1004C>T	p.Thr335Met	missense_variant	11/12	1	NM_144969.3	P1
ZDHHC15	ENST00000541184.1	c.977C>T	p.Thr326Met	missense_variant	10/11	2

Frequencies

GnomAD3 genomes AF: 0.000179 AC: 20 AN: 111822 Hom.: 0 Cov.: 23 AF XY: 0.000118 AC XY: 4 AN XY: 33998

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

GnomAD3 exomes AF: 0.000126 AC: 23 AN: 183017 Hom.: 0 AF XY: 0.0000444 AC XY: 3 AN XY: 67545

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000110

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000720 AC: 79 AN: 1097623 Hom.: 0 Cov.: 30 AF XY: 0.0000578 AC XY: 21 AN XY: 363073

Gnomad4 AFR exome AF: 0.000720

Gnomad4 AMR exome AF: 0.000199

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000994

Gnomad4 SAS exome AF: 0.0000554

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000475

Gnomad4 OTH exome AF: 0.000109

GnomAD4 genome AF: 0.000179 AC: 20 AN: 111875 Hom.: 0 Cov.: 23 AF XY: 0.000117 AC XY: 4 AN XY: 34061

Gnomad4 AFR AF: 0.000454

Gnomad4 AMR AF: 0.000190

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000377

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000564

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000702 Hom.: 3

Bravo AF: 0.000185

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000782 AC: 3

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.0000824 AC: 10

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 27, 2024

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	T
BayesDel_noAF	Benign	-0.83
Cadd	Benign	12
Dann	Benign	0.93
DEOGEN2	Benign	0.083	T;.
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.72	T;T
M_CAP	Benign	0.0076	T
MetaRNN	Benign	0.023	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-1.5	N;.
MutationTaster	Benign	1.0	D;N;N
PrimateAI	Benign	0.44	T
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	T
GERP RS		2.9
Varity_R		0.024
gMVP		0.29

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

LitVar

Other links and lift over

dbSNP: rs148698894; hg19: chrX-74598997; COSMIC: COSV64902170;