rs28382739

Variant names:

• chrX-123906879-C-T
• rs28382739
• NM_001167.4:c.1301-109C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001167.4(XIAP):​c.1301-109C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.212 in 920,074 control chromosomes in the GnomAD database, including 15,065 homozygotes. There are 58,099 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.20 (1514 hom., 6907 hem., cov: 23)
  • Exomes 𝑓: 0.21 (13551 hom. 51192 hem.)
• Consequence: XIAP NM_001167.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.49
• Publications: 1 publications found

Genes affected

XIAP (HGNC:592): (X-linked inhibitor of apoptosis) This gene encodes a protein that belongs to a family of apoptotic suppressor proteins. Members of this family share a conserved motif termed, baculovirus IAP repeat, which is necessary for their anti-apoptotic function. This protein functions through binding to tumor necrosis factor receptor-associated factors TRAF1 and TRAF2 and inhibits apoptosis induced by menadione, a potent inducer of free radicals, and interleukin 1-beta converting enzyme. This protein also inhibits at least two members of the caspase family of cell-death proteases, caspase-3 and caspase-7. Mutations in this gene are the cause of X-linked lymphoproliferative syndrome. Alternate splicing results in multiple transcript variants. Pseudogenes of this gene are found on chromosomes 2 and 11.[provided by RefSeq, Feb 2011]

XIAP Gene-Disease associations (from GenCC):

• X-linked lymphoproliferative disease due to XIAP deficiency

  Inheritance: XL Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.372 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XIAP	NM_001167.4	c.1301-109C>T		intron_variant	Intron 6 of 6	ENST00000371199.8	NP_001158.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XIAP	ENST00000371199.8	c.1301-109C>T		intron_variant	Intron 6 of 6	1	NM_001167.4	ENSP00000360242.3

Frequencies

GnomAD3 genomes AF: 0.196 AC: 21940 AN: 111655 Hom.: 1514 Cov.: 23

Gnomad AFR AF: 0.145

Gnomad AMI AF: 0.168

Gnomad AMR AF: 0.224

Gnomad ASJ AF: 0.213

Gnomad EAS AF: 0.337

Gnomad SAS AF: 0.392

Gnomad FIN AF: 0.257

Gnomad MID AF: 0.316

Gnomad NFE AF: 0.194

Gnomad OTH AF: 0.204

GnomAD4 exome AF: 0.214 AC: 172663 AN: 808365 Hom.: 13551 AF XY: 0.230 AC XY: 51192 AN XY: 222279

African (AFR) AF: 0.148 AC: 2984 AN: 20128

American (AMR) AF: 0.221 AC: 6256 AN: 28302

Ashkenazi Jewish (ASJ) AF: 0.226 AC: 3581 AN: 15844

East Asian (EAS) AF: 0.305 AC: 8724 AN: 28608

South Asian (SAS) AF: 0.395 AC: 17127 AN: 43357

European-Finnish (FIN) AF: 0.243 AC: 9269 AN: 38139

Middle Eastern (MID) AF: 0.297 AC: 850 AN: 2866

European-Non Finnish (NFE) AF: 0.195 AC: 115896 AN: 595007

Other (OTH) AF: 0.221 AC: 7976 AN: 36114

GnomAD4 genome AF: 0.196 AC: 21947 AN: 111709 Hom.: 1514 Cov.: 23 AF XY: 0.204 AC XY: 6907 AN XY: 33935

African (AFR) AF: 0.145 AC: 4460 AN: 30849

American (AMR) AF: 0.224 AC: 2332 AN: 10422

Ashkenazi Jewish (ASJ) AF: 0.213 AC: 564 AN: 2643

East Asian (EAS) AF: 0.337 AC: 1194 AN: 3539

South Asian (SAS) AF: 0.392 AC: 1063 AN: 2712

European-Finnish (FIN) AF: 0.257 AC: 1531 AN: 5966

Middle Eastern (MID) AF: 0.315 AC: 68 AN: 216

European-Non Finnish (NFE) AF: 0.194 AC: 10300 AN: 53158

Other (OTH) AF: 0.210 AC: 321 AN: 1526

Alfa AF: 0.191 Hom.: 1131

Bravo AF: 0.193

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.33
DANN	Benign	0.72
PhyloP100		-1.5
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: rs28382739; hg19: chrX-123040729; COSMIC: COSV63022430;