X-123907295-GAA-GA

Variant names:

• chrX-123907295-GA-G
• rs28382741
• NM_001167.4:c.*122delA

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_001167.4(XIAP):​c.*122delA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000218 in 664,583 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 39 hemizygotes in GnomAD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000036 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 0.00025 (0 hom. 38 hem.)
• Consequence: XIAP NM_001167.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.690
• Publications: 2 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 -8 ACMG points.

• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000036 (4/111221) while in subpopulation EAS AF = 0.00112 (4/3578). AF 95% confidence interval is 0.000381. There are 0 homozygotes in GnomAd4. There are 1 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Hemizygotes in GnomAdExome4 at 38 XL gene

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.*122delA		3_prime_UTR	Exon 7 of 7	NP_001158.2
	XIAP	NR_037916.2		n.980delA		non_coding_transcript_exon	Exon 6 of 6
	XIAP	NR_165803.1		n.962delA		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.*122delA		3_prime_UTR	Exon 7 of 7	ENSP00000360242.3
	XIAP	ENST00000698505.1		n.1061delA		non_coding_transcript_exon	Exon 2 of 2
	XIAP	ENST00000355640.3	TSL:5	c.*122delA		3_prime_UTR	Exon 7 of 7	ENSP00000347858.3

Frequencies

GnomAD3 genomes AF: 0.0000360 AC: 4 AN: 111168 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00111

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000770 AC: 8 AN: 103914 AF XY: 0.0000618

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000564

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000613

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000485

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000255 AC: 141 AN: 553362 Hom.: 0 Cov.: 9 AF XY: 0.000242 AC XY: 38 AN XY: 157266

African (AFR) AF: 0.00 AC: 0 AN: 14777

American (AMR) AF: 0.0000390 AC: 1 AN: 25650

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15319

East Asian (EAS) AF: 0.00471 AC: 117 AN: 24867

South Asian (SAS) AF: 0.00 AC: 0 AN: 38350

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35442

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

European-Non Finnish (NFE) AF: 0.0000569 AC: 21 AN: 368990

Other (OTH) AF: 0.0000722 AC: 2 AN: 27714

GnomAD4 genome AF: 0.0000360 AC: 4 AN: 111221 Hom.: 0 Cov.: 23 AF XY: 0.0000297 AC XY: 1 AN XY: 33621

African (AFR) AF: 0.00 AC: 0 AN: 30700

American (AMR) AF: 0.00 AC: 0 AN: 10404

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2644

East Asian (EAS) AF: 0.00112 AC: 4 AN: 3578

South Asian (SAS) AF: 0.00 AC: 0 AN: 2744

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5830

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 52927

Other (OTH) AF: 0.00 AC: 0 AN: 1502

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000453

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.69
Mutation Taster		=100/0	polymorphism

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;