chrX-123912422-A-T

Variant names:

• chrX-123912422-A-T
• rs5958343
• NM_001167.4:c.*5241A>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001167.4(XIAP):​c.*5241A>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.59 (13895 hom., 17356 hem., cov: 20)
  • Exomes 𝑓: 0.57 (21417 hom. 49127 hem.)
  • Failed GnomAD Quality Control
• Consequence: XIAP NM_001167.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.26
• Publications: 6 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.06).
• BP6: Variant X-123912422-A-T is Benign according to our data. Variant chrX-123912422-A-T is described in ClinVar as Benign. ClinVar VariationId is 367848.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.661 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.*5241A>T		3_prime_UTR	Exon 7 of 7	NP_001158.2
	XIAP	NM_001204401.2		c.*5241A>T		3_prime_UTR	Exon 7 of 7	NP_001191330.1	P98170
	XIAP	NM_001378590.1		c.*5241A>T		3_prime_UTR	Exon 7 of 7	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.*5241A>T		3_prime_UTR	Exon 7 of 7	ENSP00000360242.3	P98170
	XIAP	ENST00000355640.3	TSL:5	c.*5241A>T		3_prime_UTR	Exon 7 of 7	ENSP00000347858.3	P98170

Frequencies

GnomAD3 genomes AF: 0.591 AC: 63440 AN: 107376 Hom.: 13896 Cov.: 20

Gnomad AFR AF: 0.670

Gnomad AMI AF: 0.434

Gnomad AMR AF: 0.583

Gnomad ASJ AF: 0.533

Gnomad EAS AF: 0.420

Gnomad SAS AF: 0.558

Gnomad FIN AF: 0.641

Gnomad MID AF: 0.611

Gnomad NFE AF: 0.560

Gnomad OTH AF: 0.583

GnomAD2 exomes AF: 0.565 AC: 52434 AN: 92733 AF XY: 0.565

Gnomad AFR exome AF: 0.674

Gnomad AMR exome AF: 0.551

Gnomad ASJ exome AF: 0.545

Gnomad EAS exome AF: 0.468

Gnomad FIN exome AF: 0.648

Gnomad NFE exome AF: 0.563

Gnomad OTH exome AF: 0.563

GnomAD4 exome AF: 0.571 AC: 123226 AN: 215728 Hom.: 21417 Cov.: 0 AF XY: 0.572 AC XY: 49127 AN XY: 85938

African (AFR) AF: 0.678 AC: 4626 AN: 6828

American (AMR) AF: 0.549 AC: 11769 AN: 21427

Ashkenazi Jewish (ASJ) AF: 0.545 AC: 4348 AN: 7976

East Asian (EAS) AF: 0.455 AC: 3038 AN: 6683

South Asian (SAS) AF: 0.593 AC: 21137 AN: 35623

European-Finnish (FIN) AF: 0.653 AC: 6140 AN: 9398

Middle Eastern (MID) AF: 0.569 AC: 467 AN: 821

European-Non Finnish (NFE) AF: 0.564 AC: 65697 AN: 116539

Other (OTH) AF: 0.575 AC: 6004 AN: 10433

GnomAD4 genome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.591 AC: 63466 AN: 107408 Hom.: 13895 Cov.: 20 AF XY: 0.580 AC XY: 17356 AN XY: 29940

African (AFR) AF: 0.670 AC: 19796 AN: 29539

American (AMR) AF: 0.583 AC: 5736 AN: 9843

Ashkenazi Jewish (ASJ) AF: 0.533 AC: 1389 AN: 2608

East Asian (EAS) AF: 0.421 AC: 1447 AN: 3441

South Asian (SAS) AF: 0.560 AC: 1402 AN: 2504

European-Finnish (FIN) AF: 0.641 AC: 3173 AN: 4947

Middle Eastern (MID) AF: 0.612 AC: 126 AN: 206

European-Non Finnish (NFE) AF: 0.560 AC: 29251 AN: 52191

Other (OTH) AF: 0.585 AC: 862 AN: 1474

Alfa AF: 0.568 Hom.: 6068

Bravo AF: 0.596

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	X-linked lymphoproliferative disease due to XIAP deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.3
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs5958343; hg19: chrX-123046272;