rs777303823

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BS2

The NM_001167.4(XIAP):​c.844G>A​(p.Glu282Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000175 in 1,203,165 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., 2 hem., cov: 23)
Exomes 𝑓: 0.0000082 ( 0 hom. 0 hem. )

Consequence

XIAP
NM_001167.4 missense

Scores

6
6
5

Clinical Significance

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

Conservation

PhyloP100: 9.34
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PP3
MetaRNN computational evidence supports a deleterious effect, 0.773
BS2
High Hemizygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
XIAPNM_001167.4 linkc.844G>A p.Glu282Lys 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
XIAPENST00000371199.8 linkc.844G>A p.Glu282Lys missense_variant Exon 2 of 7 1 NM_001167.4 ENSP00000360242.3 P98170

Frequencies

GnomAD3 genomes
AF:
0.000107
AC:
12
AN:
111686
Hom.:
0
Cov.:
23
AF XY:
0.0000590
AC XY:
2
AN XY:
33880
show subpopulations
Gnomad AFR
AF:
0.000358
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:
0.0000188
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000339
AC:
6
AN:
177168
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
65302
show subpopulations
Gnomad AFR exome
AF:
0.000474
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS 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:
0.00000825
AC:
9
AN:
1091479
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
360797
show subpopulations
Gnomad4 AFR exome
AF:
0.000265
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000238
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.000107
AC:
12
AN:
111686
Hom.:
0
Cov.:
23
AF XY:
0.0000590
AC XY:
2
AN XY:
33880
show subpopulations
Gnomad4 AFR
AF:
0.000358
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000188
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000680
Hom.:
0
Bravo
AF:
0.000140
ExAC
AF:
0.0000247
AC:
3

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:3Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)May 18, 2016- -
Autoinflammatory syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGenome Diagnostics Laboratory, The Hospital for Sick ChildrenDec 12, 2016- -
X-linked lymphoproliferative disease due to XIAP deficiency;C5399825:X-linked lymphoproliferative disease due to SH2D1A deficiency Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsOct 31, 2018- -
X-linked lymphoproliferative disease due to XIAP deficiency Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 27, 2025- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.19
BayesDel_addAF
Pathogenic
0.19
D
BayesDel_noAF
Pathogenic
0.38
CADD
Uncertain
25
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.24
T;T;T
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Benign
0.83
T;.;.
M_CAP
Uncertain
0.29
D
MetaRNN
Pathogenic
0.77
D;D;D
MetaSVM
Uncertain
-0.0043
T
MutationAssessor
Benign
2.0
M;M;M
PrimateAI
Uncertain
0.71
T
PROVEAN
Uncertain
-2.8
D;D;D
REVEL
Pathogenic
0.70
Sift
Uncertain
0.0030
D;D;D
Sift4G
Uncertain
0.0090
D;D;D
Polyphen
1.0
D;D;D
Vest4
0.68
MutPred
0.69
Gain of MoRF binding (P = 0.0043);Gain of MoRF binding (P = 0.0043);Gain of MoRF binding (P = 0.0043);
MVP
0.85
MPC
0.85
ClinPred
0.55
D
GERP RS
5.8
Varity_R
0.95
gMVP
0.87

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.

Other links and lift over

dbSNP: rs777303823; hg19: chrX-123020356; API