X-75421896-C-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_144969.3(ZDHHC15):c.831G>C(p.Lys277Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000795 in 1,208,248 control chromosomes in the GnomAD database, including 1 homozygotes. There are 296 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00050 (0 hom., 15 hem., cov: 21)
  • Exomes 𝑓: 0.00082 (1 hom. 281 hem.)
• Consequence: ZDHHC15 NM_144969.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.265

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013935924).
• BP6: Variant X-75421896-C-G is Benign according to our data. Variant chrX-75421896-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 252786.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-75421896-C-G is described in Lovd as [Benign].
• BS2: High Hemizygotes in GnomAd at 15 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ZDHHC15	NM_144969.3	c.831G>C	p.Lys277Asn	missense_variant	9/12	ENST00000373367.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ZDHHC15	ENST00000373367.8	c.831G>C	p.Lys277Asn	missense_variant	9/12	1	NM_144969.3	P1
ZDHHC15	ENST00000541184.1	c.804G>C	p.Lys268Asn	missense_variant	8/11	2

Frequencies

GnomAD3 genomes AF: 0.000504 AC: 56 AN: 111176 Hom.: 0 Cov.: 21 AF XY: 0.000449 AC XY: 15 AN XY: 33392

Gnomad AFR AF: 0.000131

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000193

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: 0.000943

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000444 AC: 81 AN: 182384 Hom.: 0 AF XY: 0.000388 AC XY: 26 AN XY: 66988

Gnomad AFR exome AF: 0.000306

Gnomad AMR exome AF: 0.000221

Gnomad ASJ exome AF: 0.000402

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000810

Gnomad OTH exome AF: 0.000446

GnomAD4 exome AF: 0.000825 AC: 905 AN: 1097072 Hom.: 1 Cov.: 29 AF XY: 0.000775 AC XY: 281 AN XY: 362764

Gnomad4 AFR exome AF: 0.000114

Gnomad4 AMR exome AF: 0.000228

Gnomad4 ASJ exome AF: 0.000414

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00101

Gnomad4 OTH exome AF: 0.000695

GnomAD4 genome AF: 0.000504 AC: 56 AN: 111176 Hom.: 0 Cov.: 21 AF XY: 0.000449 AC XY: 15 AN XY: 33392

Gnomad4 AFR AF: 0.000131

Gnomad4 AMR AF: 0.000193

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000943

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000763 Hom.: 6

Bravo AF: 0.000484

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00138 AC: 4

ESP6500AA AF: 0.00104 AC: 4

ESP6500EA AF: 0.00134 AC: 9

ExAC AF: 0.000420 AC: 51

EpiCase AF: 0.000875

EpiControl AF: 0.000833

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Aug 24, 2015	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2022	ZDHHC15: BP4, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.85	T
BayesDel_noAF	Benign	-1.0
Cadd	Benign	12
Dann	Benign	0.97
DEOGEN2	Benign	0.068	T;.
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.73	T;T
M_CAP	Benign	0.0023	T
MetaRNN	Benign	0.014	T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-1.1	N;.
MutationTaster	Benign	1.0	D;N;N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	0.55	N;N
REVEL	Benign	0.057
Sift	Benign	0.55	T;T
Sift4G	Benign	0.37	T;T
Polyphen		0.0	B;.
Vest4		0.17
MutPred		0.47		Loss of methylation at K277 (P = 0.0064);.;
MVP		0.15
MPC		0.44
ClinPred		0.0064	T
GERP RS		-1.8
Varity_R		0.074
gMVP		0.34

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: rs145401990; hg19: chrX-74641731;