X-75421980-G-A

Variant names:

• chrX-75421980-G-A
• rs147278537
• NM_144969.3:c.747C>T

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_144969.3(ZDHHC15):​c.747C>T​(p.Cys249Cys) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000874 in 1,206,364 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 343 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00044 (0 hom., 10 hem., cov: 22)
  • Exomes 𝑓: 0.00092 (0 hom. 333 hem.)
• Consequence: ZDHHC15 NM_144969.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.106
• 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant X-75421980-G-A is Benign according to our data. Variant chrX-75421980-G-A is described in ClinVar as [Benign]. Clinvar id is 199186.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.106 with no splicing effect.
• BS2: High Hemizygotes in GnomAd4 at 10 XL,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZDHHC15	NM_144969.3	c.747C>T	p.Cys249Cys	synonymous_variant	Exon 9 of 12	ENST00000373367.8	NP_659406.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ZDHHC15	ENST00000373367.8	c.747C>T	p.Cys249Cys	synonymous_variant	Exon 9 of 12	1	NM_144969.3	ENSP00000362465.3
ZDHHC15	ENST00000541184.1	c.720C>T	p.Cys240Cys	synonymous_variant	Exon 8 of 11	2		ENSP00000445420.1

Frequencies

GnomAD3 genomes AF: 0.000439 AC: 49 AN: 111733 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.000293

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: 0.000752

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000537 AC: 96 AN: 178820 AF XY: 0.000581

Gnomad AFR exome AF: 0.000312

Gnomad AMR exome AF: 0.000113

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000885

Gnomad OTH exome AF: 0.000459

GnomAD4 exome AF: 0.000918 AC: 1005 AN: 1094631 Hom.: 0 Cov.: 30 AF XY: 0.000924 AC XY: 333 AN XY: 360539

African (AFR) AF: 0.0000763 AC: 2 AN: 26224

American (AMR) AF: 0.0000862 AC: 3 AN: 34797

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19194

East Asian (EAS) AF: 0.00 AC: 0 AN: 30066

South Asian (SAS) AF: 0.000749 AC: 40 AN: 53438

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40438

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4112

European-Non Finnish (NFE) AF: 0.00108 AC: 911 AN: 840444

Other (OTH) AF: 0.00107 AC: 49 AN: 45918

GnomAD4 genome AF: 0.000439 AC: 49 AN: 111733 Hom.: 0 Cov.: 22 AF XY: 0.000295 AC XY: 10 AN XY: 33915

African (AFR) AF: 0.000293 AC: 9 AN: 30741

American (AMR) AF: 0.00 AC: 0 AN: 10440

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2646

East Asian (EAS) AF: 0.00 AC: 0 AN: 3547

South Asian (SAS) AF: 0.00 AC: 0 AN: 2637

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6106

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

European-Non Finnish (NFE) AF: 0.000752 AC: 40 AN: 53189

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

Alfa AF: 0.000391 Hom.: 2

Bravo AF: 0.000521

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Aug 05, 2019

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 06, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	8.1
DANN	Benign	0.64
PhyloP100		0.11
Mutation Taster		=100/0	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: rs147278537; hg19: chrX-74641815;