rs199683465

Positions:

• chrX-123891304-TGAG-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PM4_Supporting BP6 BS1 BS2

The NM_001167.4(XIAP):​c.1048_1050del​(p.Glu350del) variant causes a 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 inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:3
• Conservation: PhyloP100: 1.49

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]

ACMG classification

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=2, Uncertain_significance=1, Benign=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/exons	MANE	UniProt
XIAP	NM_001167.4	c.1048_1050del	p.Glu350del	inframe_deletion	4/7	ENST00000371199.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
XIAP	ENST00000371199.8	c.1048_1050del	p.Glu350del	inframe_deletion	4/7	1	NM_001167.4	P1

Frequencies

GnomAD3 genomes AF: 0.000322 AC: 36 AN: 111923 Hom.: 1 Cov.: 22 AF XY: 0.000235 AC XY: 8 AN XY: 34085

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: 42 AN: 167419 Hom.: 0 AF XY: 0.000270 AC XY: 15 AN XY: 55583

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.: 11 AF XY: 0.000728 AC XY: 194 AN XY: 266339

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

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.: 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

Uncertain significance, criteria provided, single submitter	reference population	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	Mar 18, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 19, 2024	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 05, 2017	- -

XIAP-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 14, 2023

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

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 02, 2023

See Variant Classification Assertion Criteria. -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs199683465; hg19: chrX-123025154;