X-123906813-T-C

Variant names:

• chrX-123906813-T-C
• rs17334739
• NM_001167.4:c.1301-175T>C

Variant summary

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

The NM_001167.4(XIAP):​c.1301-175T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.194 in 111,423 control chromosomes in the GnomAD database, including 1,486 homozygotes. There are 6,692 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 0.19 (1486 hom., 6692 hem., cov: 23)
• Consequence: XIAP NM_001167.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.291
• 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=-0.8).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.367 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001167.4. 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
	XIAP	NM_001167.4	MANE Select	c.1301-175T>C		intron	N/A	NP_001158.2
	XIAP	NM_001204401.2		c.1301-175T>C		intron	N/A	NP_001191330.1
	XIAP	NM_001378590.1		c.1301-175T>C		intron	N/A	NP_001365519.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XIAP	ENST00000371199.8	TSL:1 MANE Select	c.1301-175T>C		intron	N/A	ENSP00000360242.3
	XIAP	ENST00000497640.1	TSL:1	n.523-175T>C		intron	N/A
	XIAP	ENST00000355640.3	TSL:5	c.1301-175T>C		intron	N/A	ENSP00000347858.3

Frequencies

GnomAD3 genomes AF: 0.194 AC: 21593 AN: 111369 Hom.: 1486 Cov.: 23

Gnomad AFR AF: 0.143

Gnomad AMI AF: 0.167

Gnomad AMR AF: 0.221

Gnomad ASJ AF: 0.182

Gnomad EAS AF: 0.337

Gnomad SAS AF: 0.386

Gnomad FIN AF: 0.254

Gnomad MID AF: 0.314

Gnomad NFE AF: 0.192

Gnomad OTH AF: 0.200

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.194 AC: 21599 AN: 111423 Hom.: 1486 Cov.: 23 AF XY: 0.199 AC XY: 6692 AN XY: 33665

African (AFR) AF: 0.143 AC: 4389 AN: 30714

American (AMR) AF: 0.221 AC: 2302 AN: 10410

Ashkenazi Jewish (ASJ) AF: 0.182 AC: 482 AN: 2644

East Asian (EAS) AF: 0.337 AC: 1191 AN: 3532

South Asian (SAS) AF: 0.386 AC: 1033 AN: 2673

European-Finnish (FIN) AF: 0.254 AC: 1511 AN: 5960

Middle Eastern (MID) AF: 0.312 AC: 68 AN: 218

European-Non Finnish (NFE) AF: 0.192 AC: 10198 AN: 53084

Other (OTH) AF: 0.206 AC: 312 AN: 1512

Alfa AF: 0.0579 Hom.: 259

Bravo AF: 0.191

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	1.3
DANN	Benign	0.70
PhyloP100		-0.29
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: rs17334739; hg19: chrX-123040663;