X-75478992-TAAA-TAAAA

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_144969.3(ZDHHC15):​c.164-8dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00688 in 1,038,903 control chromosomes in the GnomAD database, including 21 homozygotes. There are 1,108 hemizygotes in GnomAD. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0045 (0 hom., 145 hem., cov: 22)
  • Exomes 𝑓: 0.0072 (21 hom. 963 hem.)
• Consequence: ZDHHC15 NM_144969.3 splice_region, intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U: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 -5 ACMG points.

• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00447 (482/107905) while in subpopulation SAS AF = 0.0337 (85/2521). AF 95% confidence interval is 0.0279. There are 0 homozygotes in GnomAd4. There are 145 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Hemizygotes in GnomAd4 at 145 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.164-8dupT		splice_region intron	N/A	NP_659406.1
	ZDHHC15	NM_001146256.2		c.137-8dupT		splice_region intron	N/A	NP_001139728.1
	ZDHHC15	NM_001146257.2		c.137-8dupT		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.164-8_164-7insT		splice_region intron	N/A	ENSP00000362465.3
	ZDHHC15	ENST00000858993.1		c.164-8_164-7insT		splice_region intron	N/A	ENSP00000529052.1
	ZDHHC15	ENST00000858994.1		c.164-8_164-7insT		splice_region intron	N/A	ENSP00000529053.1

Frequencies

GnomAD3 genomes AF: 0.00447 AC: 482 AN: 107869 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00154

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00279

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0101

Gnomad SAS AF: 0.0336

Gnomad FIN AF: 0.00485

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00501

Gnomad OTH AF: 0.00209

GnomAD2 exomes AF: 0.00972 AC: 945 AN: 97221 AF XY: 0.00453

Gnomad AFR exome AF: 0.00407

Gnomad AMR exome AF: 0.00799

Gnomad ASJ exome AF: 0.00217

Gnomad EAS exome AF: 0.0175

Gnomad FIN exome AF: 0.00555

Gnomad NFE exome AF: 0.00714

Gnomad OTH exome AF: 0.0110

GnomAD4 exome AF: 0.00716 AC: 6670 AN: 930998 Hom.: 21 Cov.: 18 AF XY: 0.00357 AC XY: 963 AN XY: 269700

African (AFR) AF: 0.00413 AC: 89 AN: 21570

American (AMR) AF: 0.00469 AC: 118 AN: 25151

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 28 AN: 16198

East Asian (EAS) AF: 0.00895 AC: 237 AN: 26477

South Asian (SAS) AF: 0.0278 AC: 1156 AN: 41635

European-Finnish (FIN) AF: 0.00442 AC: 159 AN: 35958

Middle Eastern (MID) AF: 0.00305 AC: 10 AN: 3278

European-Non Finnish (NFE) AF: 0.00635 AC: 4586 AN: 721655

Other (OTH) AF: 0.00734 AC: 287 AN: 39076

GnomAD4 genome AF: 0.00447 AC: 482 AN: 107905 Hom.: 0 Cov.: 22 AF XY: 0.00462 AC XY: 145 AN XY: 31397

African (AFR) AF: 0.00154 AC: 46 AN: 29885

American (AMR) AF: 0.00279 AC: 28 AN: 10041

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2571

East Asian (EAS) AF: 0.0101 AC: 35 AN: 3450

South Asian (SAS) AF: 0.0337 AC: 85 AN: 2521

European-Finnish (FIN) AF: 0.00485 AC: 26 AN: 5364

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 210

European-Non Finnish (NFE) AF: 0.00501 AC: 259 AN: 51738

Other (OTH) AF: 0.00206 AC: 3 AN: 1453

Alfa AF: 0.00889 Hom.: 21

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
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: COSV64903285;