X-123900377-A-G

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BP6_Very_Strong

The NM_001167.4(XIAP):​c.1100-116A>G variant causes a intron 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 0.58 (13383 hom., 19178 hem., cov: 23)
  • Exomes 𝑓: 0.57 (65243 hom. 91629 hem.)
  • Failed GnomAD Quality Control
• Consequence: XIAP NM_001167.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.186
• 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: Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant X-123900377-A-G is Benign according to our data. Variant chrX-123900377-A-G is described in ClinVar as Benign. ClinVar VariationId is 1178358.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XIAP	NM_001167.4	c.1100-116A>G		intron_variant	Intron 5 of 6	ENST00000371199.8	NP_001158.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XIAP	ENST00000371199.8	c.1100-116A>G		intron_variant	Intron 5 of 6	1	NM_001167.4	ENSP00000360242.3

Frequencies

GnomAD3 genomes AF: 0.584 AC: 64594 AN: 110531 Hom.: 13383 Cov.: 23

Gnomad AFR AF: 0.637

Gnomad AMI AF: 0.432

Gnomad AMR AF: 0.582

Gnomad ASJ AF: 0.534

Gnomad EAS AF: 0.423

Gnomad SAS AF: 0.563

Gnomad FIN AF: 0.661

Gnomad MID AF: 0.608

Gnomad NFE AF: 0.563

Gnomad OTH AF: 0.581

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.571 AC: 318451 AN: 557912 Hom.: 65243 AF XY: 0.578 AC XY: 91629 AN XY: 158594

African (AFR) AF: 0.641 AC: 8986 AN: 14012

American (AMR) AF: 0.561 AC: 10453 AN: 18628

Ashkenazi Jewish (ASJ) AF: 0.538 AC: 7174 AN: 13340

East Asian (EAS) AF: 0.367 AC: 9000 AN: 24495

South Asian (SAS) AF: 0.596 AC: 19712 AN: 33069

European-Finnish (FIN) AF: 0.652 AC: 22799 AN: 34957

Middle Eastern (MID) AF: 0.577 AC: 1025 AN: 1776

European-Non Finnish (NFE) AF: 0.573 AC: 223503 AN: 390233

Other (OTH) AF: 0.577 AC: 15799 AN: 27402

GnomAD4 genome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.585 AC: 64636 AN: 110580 Hom.: 13383 Cov.: 23 AF XY: 0.584 AC XY: 19178 AN XY: 32858

African (AFR) AF: 0.637 AC: 19378 AN: 30438

American (AMR) AF: 0.582 AC: 5999 AN: 10312

Ashkenazi Jewish (ASJ) AF: 0.534 AC: 1405 AN: 2629

East Asian (EAS) AF: 0.423 AC: 1486 AN: 3512

South Asian (SAS) AF: 0.566 AC: 1519 AN: 2684

European-Finnish (FIN) AF: 0.661 AC: 3795 AN: 5741

Middle Eastern (MID) AF: 0.606 AC: 131 AN: 216

European-Non Finnish (NFE) AF: 0.563 AC: 29755 AN: 52872

Other (OTH) AF: 0.583 AC: 881 AN: 1512

Alfa AF: 0.573 Hom.: 4407

Bravo AF: 0.584

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jun 19, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.26
DANN	Benign	0.67
PhyloP100		-0.19
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: rs5958338; hg19: chrX-123034227; COSMIC: COSV63024519;