X-123907295-GAA-G

Variant names:

• chrX-123907295-GAA-G
• rs28382741
• NM_001167.4:c.*121_*122delAA

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001167.4(XIAP):​c.*121_*122delAA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000181 in 553,538 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. 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 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.690
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.*121_*122delAA		3_prime_UTR	Exon 7 of 7	NP_001158.2
	XIAP	NR_037916.2		n.979_980delAA		non_coding_transcript_exon	Exon 6 of 6
	XIAP	NR_165803.1		n.961_962delAA		non_coding_transcript_exon	Exon 8 of 8

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XIAP	ENST00000371199.8	TSL:1 MANE Select	c.*121_*122delAA		3_prime_UTR	Exon 7 of 7	ENSP00000360242.3
	XIAP	ENST00000698505.1		n.1060_1061delAA		non_coding_transcript_exon	Exon 2 of 2
	XIAP	ENST00000355640.3	TSL:5	c.*121_*122delAA		3_prime_UTR	Exon 7 of 7	ENSP00000347858.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000181 AC: 1 AN: 553538 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 157386

African (AFR) AF: 0.00 AC: 0 AN: 14778

American (AMR) AF: 0.00 AC: 0 AN: 25654

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15324

East Asian (EAS) AF: 0.0000402 AC: 1 AN: 24871

South Asian (SAS) AF: 0.00 AC: 0 AN: 38368

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35459

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2253

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 369111

Other (OTH) AF: 0.00 AC: 0 AN: 27720

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.69

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: rs28382741; hg19: chrX-123041145;