chrX-123900377-A-C

Variant names:

• chrX-123900377-A-C
• rs5958338
• NM_001167.4:c.1100-116A>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001167.4(XIAP):​c.1100-116A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000179 in 558,845 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples 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: not found (cov: 23)
  • Exomes 𝑓: 0.0000018 (0 hom. 0 hem.)
• Consequence: XIAP NM_001167.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.186
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).

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.1100-116A>C		intron	N/A	NP_001158.2
	XIAP	NM_001204401.2		c.1100-116A>C		intron	N/A	NP_001191330.1
	XIAP	NM_001378590.1		c.1100-116A>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.1100-116A>C		intron	N/A	ENSP00000360242.3
	XIAP	ENST00000497640.1	TSL:1	n.322-116A>C		intron	N/A
	XIAP	ENST00000698505.1		n.429A>C		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000179 AC: 1 AN: 558845 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 158677

African (AFR) AF: 0.00 AC: 0 AN: 14022

American (AMR) AF: 0.00 AC: 0 AN: 18638

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13347

East Asian (EAS) AF: 0.00 AC: 0 AN: 24508

South Asian (SAS) AF: 0.00 AC: 0 AN: 33094

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34984

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1776

European-Non Finnish (NFE) AF: 0.00000256 AC: 1 AN: 391033

Other (OTH) AF: 0.00 AC: 0 AN: 27443

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.24
DANN	Benign	0.82
PhyloP100		-0.19

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: rs5958338; hg19: chrX-123034227;