X-123886270-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5

The NM_001167.4(XIAP):​c.608G>A​(p.Cys203Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 23)
Exomes 𝑓: 9.1e-7 ( 0 hom. 1 hem. )
Failed GnomAD Quality Control

Consequence

XIAP
NM_001167.4 missense

Scores

13
3
1

Clinical Significance

Pathogenic no assertion criteria provided P: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_pathogenic. Variant got 7 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.994
PP5
Variant X-123886270-G-A is Pathogenic according to our data. Variant chrX-123886270-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 37244.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
XIAPNM_001167.4 linkuse as main transcriptc.608G>A p.Cys203Tyr missense_variant 2/7 ENST00000371199.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
XIAPENST00000371199.8 linkuse as main transcriptc.608G>A p.Cys203Tyr missense_variant 2/71 NM_001167.4 P1

Frequencies

GnomAD3 genomes
Cov.:
23
GnomAD3 exomes
AF:
0.00000545
AC:
1
AN:
183445
Hom.:
0
AF XY:
0.0000147
AC XY:
1
AN XY:
67895
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000221
GnomAD4 exome
Data not reliable, filtered out with message: AS_VQSR
AF:
9.11e-7
AC:
1
AN:
1098221
Hom.:
0
Cov.:
31
AF XY:
0.00000275
AC XY:
1
AN XY:
363575
show subpopulations
Gnomad4 AFR exome
AF:
0.00
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:
0.00000119
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
23
Alfa
AF:
0.000311
Hom.:
1

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

X-linked lymphoproliferative disease due to XIAP deficiency Pathogenic:1
Pathogenic, no assertion criteria providedliterature onlyOMIMMar 01, 2011- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.74
D
BayesDel_noAF
Pathogenic
0.83
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.55
D;D;D
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.96
D;.;.
M_CAP
Pathogenic
0.87
D
MetaRNN
Pathogenic
0.99
D;D;D
MetaSVM
Pathogenic
0.98
D
MutationAssessor
Pathogenic
4.0
H;H;H
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Pathogenic
0.83
D
PROVEAN
Pathogenic
-10
D;D;D
REVEL
Pathogenic
0.98
Sift
Pathogenic
0.0
D;D;D
Sift4G
Pathogenic
0.0
D;D;D
Polyphen
1.0
D;D;D
Vest4
0.97
MutPred
0.97
Gain of methylation at K208 (P = 0.055);Gain of methylation at K208 (P = 0.055);Gain of methylation at K208 (P = 0.055);
MVP
1.0
MPC
1.1
ClinPred
1.0
D
GERP RS
5.7
Varity_R
0.99
gMVP
0.99

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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: rs387907301; hg19: chrX-123020120; API