X-75522993-C-G

Variant names:

• chrX-75522993-C-G
• rs922985625
• NM_144969.3:c.32G>C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_144969.3(ZDHHC15):​c.32G>C​(p.Gly11Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000339 in 1,209,253 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., 0 hem., cov: 22)
  • Exomes 𝑓: 0.000035 (0 hom. 10 hem.)
• Consequence: ZDHHC15 NM_144969.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.892
• Publications: 0 publications found

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

ENSG00000302260 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.07582563).
• BS2: High Hemizygotes in GnomAdExome4 at 10 XL,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_144969.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZDHHC15	NM_144969.3	MANE Select	c.32G>C	p.Gly11Ala	missense	Exon 1 of 12	NP_659406.1
	ZDHHC15	NM_001146256.2		c.32G>C	p.Gly11Ala	missense	Exon 1 of 11	NP_001139728.1
	ZDHHC15	NM_001146257.2		c.32G>C	p.Gly11Ala	missense	Exon 1 of 3	NP_001139729.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZDHHC15	ENST00000373367.8	TSL:1 MANE Select	c.32G>C	p.Gly11Ala	missense	Exon 1 of 12	ENSP00000362465.3
	ZDHHC15	ENST00000858993.1		c.32G>C	p.Gly11Ala	missense	Exon 1 of 11	ENSP00000529052.1
	ZDHHC15	ENST00000858994.1		c.32G>C	p.Gly11Ala	missense	Exon 1 of 12	ENSP00000529053.1

Frequencies

GnomAD3 genomes AF: 0.0000268 AC: 3 AN: 111942 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00

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: 0.0000565

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000556 AC: 1 AN: 179725 AF XY: 0.00

Gnomad AFR exome AF: 0.00

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: 0.0000125

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000346 AC: 38 AN: 1097311 Hom.: 0 Cov.: 31 AF XY: 0.0000276 AC XY: 10 AN XY: 362703

African (AFR) AF: 0.0000379 AC: 1 AN: 26387

American (AMR) AF: 0.00 AC: 0 AN: 35106

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19338

East Asian (EAS) AF: 0.00 AC: 0 AN: 30185

South Asian (SAS) AF: 0.00 AC: 0 AN: 53930

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40469

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4135

European-Non Finnish (NFE) AF: 0.0000440 AC: 37 AN: 841698

Other (OTH) AF: 0.00 AC: 0 AN: 46063

GnomAD4 genome AF: 0.0000268 AC: 3 AN: 111942 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 34112

African (AFR) AF: 0.00 AC: 0 AN: 30811

American (AMR) AF: 0.00 AC: 0 AN: 10678

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2637

East Asian (EAS) AF: 0.00 AC: 0 AN: 3492

South Asian (SAS) AF: 0.00 AC: 0 AN: 2678

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6146

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 237

European-Non Finnish (NFE) AF: 0.0000565 AC: 3 AN: 53076

Other (OTH) AF: 0.00 AC: 0 AN: 1503

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000189

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	16
DANN	Benign	0.88
DEOGEN2	Benign	0.091	T
FATHMM_MKL	Benign	0.33	N
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.0077	T
MetaRNN	Benign	0.076	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.77	N
PhyloP100		0.89
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.66	N
REVEL	Benign	0.032
Sift	Benign	0.17	T
Sift4G	Benign	0.49	T
Polyphen		0.17	B
Vest4		0.077
MutPred		0.39		Loss of helix (P = 0.0376)
MVP		0.11
MPC		0.42
ClinPred		0.12	T
GERP RS		2.8
PromoterAI		0.19	Neutral
Varity_R		0.13
gMVP		0.46
Mutation Taster		=90/10	polymorphism

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

Other links and lift over

dbSNP: rs922985625; hg19: chrX-74742828;