X-75429100-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_144969.3(ZDHHC15):c.581G>A(p.Ser194Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000406 in 1,206,266 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 10 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., 5 hem., cov: 23)
  • Exomes 𝑓: 0.000024 (0 hom. 5 hem.)
• Consequence: ZDHHC15 NM_144969.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 3.15

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.028299004).
• BP6: Variant X-75429100-C-T is Benign according to our data. Variant chrX-75429100-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2378041.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
• BS2: High Hemizygotes in GnomAd at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZDHHC15	NM_144969.3	c.581G>A	p.Ser194Asn	missense_variant	7/12	ENST00000373367.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZDHHC15	ENST00000373367.8	c.581G>A	p.Ser194Asn	missense_variant	7/12	1	NM_144969.3	P1
ZDHHC15	ENST00000541184.1	c.554G>A	p.Ser185Asn	missense_variant	6/11	2

Frequencies

GnomAD3 genomes AF: 0.000216 AC: 24 AN: 111295 Hom.: 0 Cov.: 23 AF XY: 0.000149 AC XY: 5 AN XY: 33523

Gnomad AFR AF: 0.000751

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: 0.000666

GnomAD3 exomes AF: 0.0000620 AC: 11 AN: 177555 Hom.: 0 AF XY: 0.0000481 AC XY: 3 AN XY: 62423

Gnomad AFR exome AF: 0.000852

Gnomad AMR exome AF: 0.00

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: 0.0000237 AC: 26 AN: 1094918 Hom.: 0 Cov.: 30 AF XY: 0.0000139 AC XY: 5 AN XY: 360792

Gnomad4 AFR exome AF: 0.000839

Gnomad4 AMR exome AF: 0.00

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: 0.00000119

Gnomad4 OTH exome AF: 0.0000653

GnomAD4 genome AF: 0.000207 AC: 23 AN: 111348 Hom.: 0 Cov.: 23 AF XY: 0.000149 AC XY: 5 AN XY: 33586

Gnomad4 AFR AF: 0.000717

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000658

Alfa AF: 0.0000171 Hom.: 1

Bravo AF: 0.000276

ESP6500AA AF: 0.00156 AC: 6

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000577 AC: 7

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 10, 2022

The c.581G>A (p.S194N) alteration is located in exon 7 (coding exon 7) of the ZDHHC15 gene. This alteration results from a G to A substitution at nucleotide position 581, causing the serine (S) at amino acid position 194 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Nov 01, 2022

ZDHHC15: BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.71
Cadd	Benign	18
Dann	Benign	0.95
DEOGEN2	Benign	0.092	T;.
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.79	T;T
M_CAP	Benign	0.0029	T
MetaRNN	Benign	0.028	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.78	N;.
MutationTaster	Benign	1.0	D;N;N
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.090	N;N
REVEL	Benign	0.059
Sift	Benign	0.039	D;D
Sift4G	Benign	0.24	T;T
Polyphen		0.0010	B;.
Vest4		0.19
MVP		0.082
MPC		0.36
ClinPred		0.062	T
GERP RS		1.9
Varity_R		0.11
gMVP		0.59

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: rs149832160; hg19: chrX-74648935;