chrX-123891304-TGAG-T

Variant names:

• chrX-123891304-TGAG-T
• rs199683465
• NM_001167.4:c.1048_1050delGAG

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PM4_Supporting BP6 BS1 BS2

The NM_001167.4(XIAP):​c.1048_1050delGAG​(p.Glu350del) variant causes a conservative inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000612 in 1,066,224 control chromosomes in the GnomAD database, including 12 homozygotes. There are 202 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00032 (1 hom., 8 hem., cov: 22)
  • Exomes 𝑓: 0.00065 (11 hom. 194 hem.)
• Consequence: XIAP NM_001167.4 conservative_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:3
• Conservation: PhyloP100: 1.49
• Publications: 4 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.

• PM4: Nonframeshift variant in NON repetitive region in NM_001167.4. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant X-123891304-TGAG-T is Benign according to our data. Variant chrX-123891304-TGAG-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 225518.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000322 (36/111969) while in subpopulation EAS AF = 0.00973 (35/3596). AF 95% confidence interval is 0.00719. There are 1 homozygotes in GnomAd4. There are 8 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 8 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XIAP	NM_001167.4	c.1048_1050delGAG	p.Glu350del	conservative_inframe_deletion	Exon 4 of 7	ENST00000371199.8	NP_001158.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XIAP	ENST00000371199.8	c.1048_1050delGAG	p.Glu350del	conservative_inframe_deletion	Exon 4 of 7	1	NM_001167.4	ENSP00000360242.3

Frequencies

GnomAD3 genomes AF: 0.000322 AC: 36 AN: 111923 Hom.: 1 Cov.: 22

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000957

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00970

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: 0.000251 AC: 42 AN: 167419 AF XY: 0.000270

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00259

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000523

Gnomad OTH exome AF: 0.000247

GnomAD4 exome AF: 0.000647 AC: 617 AN: 954255 Hom.: 11 AF XY: 0.000728 AC XY: 194 AN XY: 266339

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000423 AC: 1 AN: 23613

American (AMR) AF: 0.00 AC: 0 AN: 32508

Ashkenazi Jewish (ASJ) AF: 0.0000556 AC: 1 AN: 17977

East Asian (EAS) AF: 0.0206 AC: 595 AN: 28852

South Asian (SAS) AF: 0.000109 AC: 5 AN: 45975

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39591

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2546

European-Non Finnish (NFE) AF: 0.0000111 AC: 8 AN: 722296

Other (OTH) AF: 0.000171 AC: 7 AN: 40897

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000322 AC: 36 AN: 111969 Hom.: 1 Cov.: 22 AF XY: 0.000234 AC XY: 8 AN XY: 34141

African (AFR) AF: 0.00 AC: 0 AN: 30889

American (AMR) AF: 0.0000956 AC: 1 AN: 10462

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2652

East Asian (EAS) AF: 0.00973 AC: 35 AN: 3596

South Asian (SAS) AF: 0.00 AC: 0 AN: 2741

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5988

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 215

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53211

Other (OTH) AF: 0.00 AC: 0 AN: 1527

Alfa AF: 0.000130 Hom.: 0

Bravo AF: 0.000121

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

X-linked lymphoproliferative disease due to XIAP deficiency Pathogenic:1 Uncertain:1 Benign:1

Dec 05, 2017

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jan 01, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 18, 2016

Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: reference population

- -

XIAP-related disorder Benign:1

Dec 14, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Mar 02, 2023

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

See Variant Classification Assertion Criteria. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.5
Mutation Taster		=72/28	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: rs199683465; hg19: chrX-123025154;