rs150317928

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001167.4(XIAP):c.455C>G(p.Thr152Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000347 in 1,209,888 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 12 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00018 ( 0 hom., 4 hem., cov: 23)

Exomes 𝑓: 0.000020 ( 0 hom. 8 hem. )

Consequence

XIAP
NM_001167.4 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.12

Publications

0 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: Orphanet, Labcorp Genetics (formerly Invitae)

XIAP links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.039372295).

BP6

Variant X-123886117-C-G is Benign according to our data. Variant chrX-123886117-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 533659.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000179 (20/111774) while in subpopulation AFR AF = 0.000649 (20/30797). AF 95% confidence interval is 0.00043. There are 0 homozygotes in GnomAd4. There are 4 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XIAP	NM_001167.4 link	c.455C>G	p.Thr152Ser	missense_variant	Exon 2 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.455C>G	p.Thr152Ser	missense_variant	Exon 2 of 7	1	NM_001167.4	ENSP00000360242.3		P98170

Frequencies

GnomAD3 genomes

AF:

0.000179

AC:

AN:

111774

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000649

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

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:

0.0000546

AC:

AN:

183083

AF XY:

0.0000592

show subpopulations

Gnomad AFR exome

AF:

0.000763

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000200

AC:

AN:

1098114

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

363482

show subpopulations

African (AFR)

AF:

0.000758

AC:

AN:

26400

American (AMR)

AF:

0.00

AC:

AN:

35207

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19386

East Asian (EAS)

AF:

0.00

AC:

AN:

30206

South Asian (SAS)

AF:

0.00

AC:

AN:

54148

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40425

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4136

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

842110

Other (OTH)

AF:

0.0000434

AC:

AN:

46096

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

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:

0.000179

AC:

AN:

111774

Hom.:

Cov.:

AF XY:

0.000118

AC XY:

AN XY:

33954

show subpopulations

African (AFR)

AF:

0.000649

AC:

AN:

30797

American (AMR)

AF:

0.00

AC:

AN:

10401

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2651

East Asian (EAS)

AF:

0.00

AC:

AN:

3594

South Asian (SAS)

AF:

0.00

AC:

AN:

2711

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6043

Middle Eastern (MID)

AF:

0.00

AC:

AN:

240

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53165

Other (OTH)

AF:

0.00

AC:

AN:

1495

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

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:

0.0000712

Hom.:

Bravo

AF:

0.000196

ESP6500AA

AF:

0.000782

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 23, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: XIAP c.455C>G (p.Thr152Ser) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.5e-05 in 183083 control chromosomes, predominantly at a frequency of 0.00076 within the African or African-American subpopulation in the gnomAD database. This frequency is not significantly higher than estimated for a pathogenic variant in XIAP causing X-Linked Lymphoproliferative Disease Due To XIAP Deficiency, allowing no conclusion about variant significance. To our knowledge, no occurrence of c.455C>G in individuals affected with X-Linked Lymphoproliferative Disease Due To XIAP Deficiency and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 533659). Based on the evidence outlined above, the variant was classified as uncertain significance. -

X-linked lymphoproliferative disease due to XIAP deficiency

Benign:1

Jul 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.091

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.62

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.018

T;.;T;T

FATHMM_MKL

Benign

0.52

LIST_S2

Benign

0.61

T;T;.;.

M_CAP

Benign

0.033

MetaRNN

Benign

0.039

T;T;T;T

MetaSVM

Benign

-0.66

MutationAssessor

Benign

1.6

L;.;L;L

PhyloP100

1.1

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.64

N;N;N;N

REVEL

Benign

0.14

Sift

Benign

0.68

T;T;T;T

Sift4G

Benign

0.91

T;T;T;T

Polyphen

0.0020

B;.;B;B

Vest4

0.070

MutPred

0.26

Loss of phosphorylation at T152 (P = 0.0531);Loss of phosphorylation at T152 (P = 0.0531);Loss of phosphorylation at T152 (P = 0.0531);Loss of phosphorylation at T152 (P = 0.0531);

MVP

0.28

MPC

0.20

ClinPred

0.039

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.36

gMVP

0.47

Mutation Taster

=100/0

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over