X-75478992-TAAA-TAA

Variant names:

• chrX-75478992-TA-T
• rs199537523
• NM_144969.3:c.164-8delT

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_Moderate BS2

The NM_144969.3(ZDHHC15):​c.164-8delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00221 in 1,039,865 control chromosomes in the GnomAD database, including 5 homozygotes. There are 277 hemizygotes in GnomAD. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00096 (1 hom., 34 hem., cov: 22)
  • Exomes 𝑓: 0.0024 (4 hom. 243 hem.)
• Consequence: ZDHHC15 NM_144969.3 splice_region, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.835
• Publications: 1 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: Likely_benign. The variant received -6 ACMG points.

• BP6: Variant X-75478992-TA-T is Benign according to our data. Variant chrX-75478992-TA-T is described in ClinVar as Benign. ClinVar VariationId is 212630.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAd4 at 34 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.164-8delT		splice_region intron	N/A	NP_659406.1
	ZDHHC15	NM_001146256.2		c.137-8delT		splice_region intron	N/A	NP_001139728.1
	ZDHHC15	NM_001146257.2		c.137-8delT		splice_region intron	N/A	NP_001139729.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ZDHHC15	ENST00000373367.8	TSL:1 MANE Select	c.164-8delT		splice_region intron	N/A	ENSP00000362465.3
	ZDHHC15	ENST00000858993.1		c.164-8delT		splice_region intron	N/A	ENSP00000529052.1
	ZDHHC15	ENST00000858994.1		c.164-8delT		splice_region intron	N/A	ENSP00000529053.1

Frequencies

GnomAD3 genomes AF: 0.000964 AC: 104 AN: 107857 Hom.: 1 Cov.: 22

Gnomad AFR AF: 0.000335

Gnomad AMI AF: 0.00298

Gnomad AMR AF: 0.000399

Gnomad ASJ AF: 0.0245

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00431

Gnomad NFE AF: 0.000367

Gnomad OTH AF: 0.00209

GnomAD2 exomes AF: 0.00590 AC: 574 AN: 97221 AF XY: 0.00189

Gnomad AFR exome AF: 0.00347

Gnomad AMR exome AF: 0.00799

Gnomad ASJ exome AF: 0.0474

Gnomad EAS exome AF: 0.00474

Gnomad FIN exome AF: 0.00238

Gnomad NFE exome AF: 0.00403

Gnomad OTH exome AF: 0.00667

GnomAD4 exome AF: 0.00235 AC: 2194 AN: 931971 Hom.: 4 Cov.: 18 AF XY: 0.000898 AC XY: 243 AN XY: 270499

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00330 AC: 71 AN: 21535

American (AMR) AF: 0.00398 AC: 100 AN: 25140

Ashkenazi Jewish (ASJ) AF: 0.0289 AC: 467 AN: 16186

East Asian (EAS) AF: 0.00132 AC: 35 AN: 26512

South Asian (SAS) AF: 0.00127 AC: 53 AN: 41867

European-Finnish (FIN) AF: 0.000751 AC: 27 AN: 35945

Middle Eastern (MID) AF: 0.00274 AC: 9 AN: 3283

European-Non Finnish (NFE) AF: 0.00181 AC: 1311 AN: 722427

Other (OTH) AF: 0.00310 AC: 121 AN: 39076

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000964 AC: 104 AN: 107894 Hom.: 1 Cov.: 22 AF XY: 0.00108 AC XY: 34 AN XY: 31386

African (AFR) AF: 0.000335 AC: 10 AN: 29886

American (AMR) AF: 0.000399 AC: 4 AN: 10037

Ashkenazi Jewish (ASJ) AF: 0.0245 AC: 63 AN: 2570

East Asian (EAS) AF: 0.000580 AC: 2 AN: 3449

South Asian (SAS) AF: 0.00 AC: 0 AN: 2519

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5366

Middle Eastern (MID) AF: 0.00476 AC: 1 AN: 210

European-Non Finnish (NFE) AF: 0.000367 AC: 19 AN: 51734

Other (OTH) AF: 0.00207 AC: 3 AN: 1451

Alfa AF: 0.0119 Hom.: 21

Bravo AF: 0.000997

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.83
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs199537523; hg19: chrX-74698827; COSMIC: COSV64902789;