X-75431518-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_144969.3(ZDHHC15):c.382G>C(p.Val128Leu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000183 in 1,091,452 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000018 (0 hom. 0 hem.)
• Consequence: ZDHHC15 NM_144969.3 missense, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.54

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20210856).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZDHHC15	NM_144969.3	c.382G>C	p.Val128Leu	missense_variant, splice_region_variant	5/12	ENST00000373367.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZDHHC15	ENST00000373367.8	c.382G>C	p.Val128Leu	missense_variant, splice_region_variant	5/12	1	NM_144969.3	P1
ZDHHC15	ENST00000541184.1	c.355G>C	p.Val119Leu	missense_variant, splice_region_variant	4/11	2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD3 exomes AF: 0.0000114 AC: 2 AN: 175635 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 61459

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000755

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS 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: 0.00000183 AC: 2 AN: 1091452 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 357534

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000576

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

Bravo AF: 0.00000756

ExAC AF: 0.00000824 AC: 1

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

Jul 09, 2021

The c.382G>C (p.V128L) alteration is located in exon 5 (coding exon 5) of the ZDHHC15 gene. This alteration results from a G to C substitution at nucleotide position 382, causing the valine (V) at amino acid position 128 to be replaced by a leucine (L). 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	0.34
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.57
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Benign	0.14	T;.
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.20	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.30	N;.
MutationTaster	Benign	0.98	D;D;D
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.12
Sift	Benign	0.071	T;T
Sift4G	Benign	0.13	T;T
Polyphen		0.0050	B;.
Vest4		0.33
MutPred		0.50		Loss of MoRF binding (P = 0.0975);.;
MVP		0.11
MPC		0.39
ClinPred		0.28	T
GERP RS		5.1
Varity_R		0.21
gMVP		0.33

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

LitVar

Other links and lift over

dbSNP: rs767470063; hg19: chrX-74651353;