X-75424765-C-T

Variant names:

• chrX-75424765-C-T
• rs377715509
• NM_144969.3:c.623G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_144969.3(ZDHHC15):​c.623G>A​(p.Arg208His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000036 in 1,196,005 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 21 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. 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. R208L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000045 (0 hom., 1 hem., cov: 22)
  • Exomes 𝑓: 0.000035 (0 hom. 20 hem.)
• Consequence: ZDHHC15 NM_144969.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.19
• 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

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.051561385).
• BS2: High Hemizygotes in GnomAdExome4 at 20 XL,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZDHHC15	NM_144969.3	c.623G>A	p.Arg208His	missense_variant	Exon 8 of 12	ENST00000373367.8	NP_659406.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZDHHC15	ENST00000373367.8	c.623G>A	p.Arg208His	missense_variant	Exon 8 of 12	1	NM_144969.3	ENSP00000362465.3
ZDHHC15	ENST00000541184.1	c.596G>A	p.Arg199His	missense_variant	Exon 7 of 11	2		ENSP00000445420.1

Frequencies

GnomAD3 genomes AF: 0.0000449 AC: 5 AN: 111280 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: 0.000847

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000168

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000188

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000429 AC: 7 AN: 163023 AF XY: 0.0000598

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000165

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000275

Gnomad OTH exome AF: 0.000246

GnomAD4 exome AF: 0.0000350 AC: 38 AN: 1084725 Hom.: 0 Cov.: 29 AF XY: 0.0000568 AC XY: 20 AN XY: 352237

African (AFR) AF: 0.00 AC: 0 AN: 25791

American (AMR) AF: 0.00 AC: 0 AN: 33542

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18991

East Asian (EAS) AF: 0.000135 AC: 4 AN: 29553

South Asian (SAS) AF: 0.0000589 AC: 3 AN: 50914

European-Finnish (FIN) AF: 0.0000747 AC: 3 AN: 40169

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4081

European-Non Finnish (NFE) AF: 0.0000299 AC: 25 AN: 836147

Other (OTH) AF: 0.0000659 AC: 3 AN: 45537

GnomAD4 genome AF: 0.0000449 AC: 5 AN: 111280 Hom.: 0 Cov.: 22 AF XY: 0.0000298 AC XY: 1 AN XY: 33542

African (AFR) AF: 0.00 AC: 0 AN: 30616

American (AMR) AF: 0.00 AC: 0 AN: 10372

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2639

East Asian (EAS) AF: 0.000847 AC: 3 AN: 3543

South Asian (SAS) AF: 0.00 AC: 0 AN: 2677

European-Finnish (FIN) AF: 0.000168 AC: 1 AN: 5948

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 235

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53062

Other (OTH) AF: 0.00 AC: 0 AN: 1501

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000340

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.0000495 AC: 6

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 08, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.623G>A (p.R208H) alteration is located in exon 8 (coding exon 8) of the ZDHHC15 gene. This alteration results from a G to A substitution at nucleotide position 623, causing the arginine (R) at amino acid position 208 to be replaced by a histidine (H). 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	0.12
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.063	T;.
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.052	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.61	N;.
PhyloP100		1.2
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	0.35	N;N
REVEL	Benign	0.052
Sift	Benign	0.32	T;T
Sift4G	Benign	0.29	T;T
Polyphen		0.13	B;.
Vest4		0.055
MVP		0.14
MPC		0.47
ClinPred		0.043	T
GERP RS		5.6
Varity_R		0.094
gMVP		0.48
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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: rs377715509; hg19: chrX-74644600; COSMIC: COSV108901663;