chrX-123885808-G-T

Variant names:

• chrX-123885808-G-T
• NM_001167.4:c.146G>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001167.4(XIAP):​c.146G>T​(p.Arg49Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,098,209 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 1 hem.)
• Consequence: XIAP NM_001167.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.02

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.754

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XIAP	NM_001167.4	c.146G>T	p.Arg49Leu	missense_variant	Exon 2 of 7	ENST00000371199.8	NP_001158.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XIAP	ENST00000371199.8	c.146G>T	p.Arg49Leu	missense_variant	Exon 2 of 7	1	NM_001167.4	ENSP00000360242.3

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1098209 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 1 AN XY: 363565

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

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Uncertain	0.082	D
BayesDel_noAF	Benign	-0.12
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T;.;T;T
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.88	D;D;.;.
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.75	D;D;D;D
MetaSVM	Uncertain	-0.076	T
MutationAssessor	Benign	1.6	L;.;L;L
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-5.3	D;D;D;D
REVEL	Uncertain	0.56
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Uncertain	0.0040	D;D;D;D
Polyphen		1.0	D;.;D;D
Vest4		0.47
MutPred		0.69		Loss of methylation at R49 (P = 0.0677);Loss of methylation at R49 (P = 0.0677);Loss of methylation at R49 (P = 0.0677);Loss of methylation at R49 (P = 0.0677);
MVP		0.63
MPC		0.93
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.84
gMVP		0.84

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-123019658;