dbSNP rs199683465: XIAP:p.Glu350del (chrX-123891304-TGAG-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -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

Publications

4 publications found

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 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

XIAP links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
XIAP	NM_001167.4	MANE Select	c.1048_1050delGAG	p.Glu350del	conservative_inframe_deletion	Exon 4 of 7	NP_001158.2
XIAP	NM_001204401.2		c.1048_1050delGAG	p.Glu350del	conservative_inframe_deletion	Exon 4 of 7	NP_001191330.1	P98170
XIAP	NM_001378590.1		c.1048_1050delGAG	p.Glu350del	conservative_inframe_deletion	Exon 4 of 7	NP_001365519.1	P98170

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
XIAP	ENST00000371199.8	TSL:1 MANE Select	c.1048_1050delGAG	p.Glu350del	conservative_inframe_deletion	Exon 4 of 7	ENSP00000360242.3	P98170
XIAP	ENST00000497640.1	TSL:1	n.270_272delGAG		non_coding_transcript_exon	Exon 3 of 6
XIAP	ENST00000355640.3	TSL:5	c.1048_1050delGAG	p.Glu350del	conservative_inframe_deletion	Exon 4 of 7	ENSP00000347858.3	P98170

Frequencies

GnomAD3 genomes

AF:

0.000322

AC:

AN:

111923

Hom.:

Cov.:

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

GnomAD2 exomes

AF:

0.000251

AC:

AN:

167419

AF XY:

0.000270

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 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

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

African (AFR)

AF:

0.0000423

AC:

AN:

23613

American (AMR)

AF:

0.00

AC:

AN:

32508

Ashkenazi Jewish (ASJ)

AF:

0.0000556

AC:

AN:

17977

East Asian (EAS)

AF:

0.0206

AC:

595

AN:

28852

South Asian (SAS)

AF:

0.000109

AC:

AN:

45975

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39591

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2546

European-Non Finnish (NFE)

AF:

0.0000111

AC:

AN:

722296

Other (OTH)

AF:

0.000171

AC:

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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.364

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000322

AC:

AN:

111969

Hom.:

Cov.:

AF XY:

0.000234

AC XY:

AN XY:

34141

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30889

American (AMR)

AF:

0.0000956

AC:

AN:

10462

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2652

East Asian (EAS)

AF:

0.00973

AC:

AN:

3596

South Asian (SAS)

AF:

0.00

AC:

AN:

2741

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5988

Middle Eastern (MID)

AF:

0.00

AC:

AN:

215

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53211

Other (OTH)

AF:

0.00

AC:

AN:

1527

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000130

Hom.:

Bravo

AF:

0.000121

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

X-linked lymphoproliferative disease due to XIAP deficiency (3)

not provided (1)

XIAP-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.5

Mutation Taster

=72/28

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over