rs199683465

Variant names:

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PM4_SupportingBP6BS1BS2

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

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1B:3

Conservation

PhyloP100: 1.49

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 225518.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=1, Uncertain_significance=1}.

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 male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.

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 link	c.1048_1050delGAG	p.Glu350del	conservative_inframe_deletion	Exon 4 of 7	ENST00000371199.8	NP_001158.2	P98170

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XIAP	ENST00000371199.8 link	c.1048_1050delGAG	p.Glu350del	conservative_inframe_deletion	Exon 4 of 7	1	NM_001167.4	ENSP00000360242.3		P98170

Frequencies

GnomAD3 genomes

AF:

0.000322

AC:

AN:

111923

Hom.:

Cov.:

AF XY:

0.000235

AC XY:

AN XY:

34085

show subpopulations

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

GnomAD3 exomes

AF:

0.000251

AC:

AN:

167419

Hom.:

AF XY:

0.000270

AC XY:

AN XY:

55583

show subpopulations

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 SAS exome

AF:

0.000257

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.:

AF XY:

0.000728

AC XY:

194

AN XY:

266339

show subpopulations

Gnomad4 AFR exome

AF:

0.0000423

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000556

Gnomad4 EAS exome

AF:

0.0206

Gnomad4 SAS exome

AF:

0.000109

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000111

Gnomad4 OTH exome

AF:

0.000171

GnomAD4 genome

AF:

0.000322

AC:

AN:

111969

Hom.:

Cov.:

AF XY:

0.000234

AC XY:

AN XY:

34141

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000956

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00973

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000130

Hom.:

Bravo

AF:

0.000121

ClinVar

Significance: Conflicting classifications of pathogenicity

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

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

X-linked lymphoproliferative disease due to XIAP deficiency

Pathogenic:1Uncertain:1Benign:1

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

- -

Dec 05, 2017

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over