chrX-123861754-T-C

Variant names:

• chrX-123861754-T-C
• rs1474593
• NM_001167.4:c.-33+1461T>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.-33+1461T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.383 in 110,953 control chromosomes in the GnomAD database, including 6,126 homozygotes. There are 12,242 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 0.38 (6126 hom., 12242 hem., cov: 23)
• Consequence: XIAP NM_001167.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.988
• 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: Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.469 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XIAP	NM_001167.4	MANE Select	c.-33+1461T>C		intron	N/A	NP_001158.2
	XIAP	NM_001204401.2		c.-33+1849T>C		intron	N/A	NP_001191330.1	P98170
	XIAP	NM_001378590.1		c.-33+1209T>C		intron	N/A	NP_001365519.1	P98170

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XIAP	ENST00000371199.8	TSL:1 MANE Select	c.-33+1461T>C		intron	N/A	ENSP00000360242.3	P98170
	XIAP	ENST00000497640.1	TSL:1	n.99+1461T>C		intron	N/A
	XIAP	ENST00000355640.3	TSL:5	c.-33+1209T>C		intron	N/A	ENSP00000347858.3	P98170

Frequencies

GnomAD3 genomes AF: 0.383 AC: 42421 AN: 110901 Hom.: 6120 Cov.: 23

Gnomad AFR AF: 0.476

Gnomad AMI AF: 0.259

Gnomad AMR AF: 0.357

Gnomad ASJ AF: 0.342

Gnomad EAS AF: 0.0843

Gnomad SAS AF: 0.172

Gnomad FIN AF: 0.391

Gnomad MID AF: 0.298

Gnomad NFE AF: 0.368

Gnomad OTH AF: 0.378

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

GnomAD4 genome AF: 0.383 AC: 42443 AN: 110953 Hom.: 6126 Cov.: 23 AF XY: 0.369 AC XY: 12242 AN XY: 33221

African (AFR) AF: 0.475 AC: 14488 AN: 30475

American (AMR) AF: 0.357 AC: 3698 AN: 10366

Ashkenazi Jewish (ASJ) AF: 0.342 AC: 903 AN: 2638

East Asian (EAS) AF: 0.0840 AC: 300 AN: 3572

South Asian (SAS) AF: 0.174 AC: 473 AN: 2713

European-Finnish (FIN) AF: 0.391 AC: 2275 AN: 5824

Middle Eastern (MID) AF: 0.298 AC: 64 AN: 215

European-Non Finnish (NFE) AF: 0.368 AC: 19504 AN: 52965

Other (OTH) AF: 0.373 AC: 563 AN: 1510

Alfa AF: 0.387 Hom.: 2582

Bravo AF: 0.389

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	8.1
DANN	Benign	0.71
PhyloP100		0.99
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: rs1474593; hg19: chrX-122995604;