X-75478992-TAAA-TAAAAA

Variant names:

• chrX-75478992-T-TAA
• rs199537523
• NM_144969.3:c.164-9_164-8dupTT

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_144969.3(ZDHHC15):​c.164-9_164-8dupTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000737 in 949,662 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000074 (0 hom. 1 hem.)
• Consequence: ZDHHC15 NM_144969.3 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• 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: Uncertain_significance. The variant received 0 ACMG points.

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.164-9_164-8dupTT		splice_region intron	N/A	NP_659406.1
	ZDHHC15	NM_001146256.2		c.137-9_137-8dupTT		splice_region intron	N/A	NP_001139728.1
	ZDHHC15	NM_001146257.2		c.137-9_137-8dupTT		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_164-7insTT		splice_region intron	N/A	ENSP00000362465.3
	ZDHHC15	ENST00000858993.1		c.164-8_164-7insTT		splice_region intron	N/A	ENSP00000529052.1
	ZDHHC15	ENST00000858994.1		c.164-8_164-7insTT		splice_region intron	N/A	ENSP00000529053.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD2 exomes AF: 0.0000411 AC: 4 AN: 97221 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000176

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000737 AC: 7 AN: 949662 Hom.: 0 Cov.: 18 AF XY: 0.00000358 AC XY: 1 AN XY: 279268

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

African (AFR) AF: 0.00 AC: 0 AN: 21959

American (AMR) AF: 0.00 AC: 0 AN: 25740

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16547

East Asian (EAS) AF: 0.00 AC: 0 AN: 27054

South Asian (SAS) AF: 0.0000930 AC: 4 AN: 43028

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36646

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3321

European-Non Finnish (NFE) AF: 0.00000408 AC: 3 AN: 735460

Other (OTH) AF: 0.00 AC: 0 AN: 39907

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000287833), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs199537523; hg19: chrX-74698827;