X-123885808-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_001167.4(XIAP):c.146G>A(p.Arg49Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000512 in 1,210,311 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 40 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., 2 hem., cov: 23)
  • Exomes 𝑓: 0.000054 (0 hom. 38 hem.)
• Consequence: XIAP NM_001167.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• 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 Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.15487641).
• BP6: Variant X-123885808-G-A is Benign according to our data. Variant chrX-123885808-G-A is described in ClinVar as [Benign]. Clinvar id is 1164151.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0000268 (3/112101) while in subpopulation SAS AF= 0.00111 (3/2703). AF 95% confidence interval is 0.000302. There are 0 homozygotes in gnomad4. There are 2 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
XIAP	NM_001167.4	c.146G>A	p.Arg49Gln	missense_variant	2/7	ENST00000371199.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
XIAP	ENST00000371199.8	c.146G>A	p.Arg49Gln	missense_variant	2/7	1	NM_001167.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000268 AC: 3 AN: 112047 Hom.: 0 Cov.: 23 AF XY: 0.0000585 AC XY: 2 AN XY: 34217

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00111

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000764 AC: 14 AN: 183339 Hom.: 0 AF XY: 0.000133 AC XY: 9 AN XY: 67889

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: 0.000734

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000537 AC: 59 AN: 1098210 Hom.: 0 Cov.: 31 AF XY: 0.000105 AC XY: 38 AN XY: 363566

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: 0.00102

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000217

GnomAD4 genome AF: 0.0000268 AC: 3 AN: 112101 Hom.: 0 Cov.: 23 AF XY: 0.0000583 AC XY: 2 AN XY: 34281

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00111

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000151

ExAC AF: 0.0000988 AC: 12

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

X-linked lymphoproliferative disease due to XIAP deficiency Benign:2

Benign, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Dec 12, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jul 19, 2023	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.47
Cadd	Benign	23
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.13	T;.;T;T
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.83	T;D;.;.
M_CAP	Uncertain	0.094	D
MetaRNN	Benign	0.15	T;T;T;T
MetaSVM	Benign	-0.31	T
MutationAssessor	Benign	0.55	N;.;N;N
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-2.5	D;D;D;D
REVEL	Uncertain	0.42
Sift	Benign	0.038	D;T;D;D
Sift4G	Uncertain	0.056	T;T;T;T
Polyphen		1.0	D;.;D;D
Vest4		0.097
MutPred		0.68		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		0.55
MPC		0.48
ClinPred		0.27	T
GERP RS		5.8
Varity_R		0.66
gMVP		0.65

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

Other links and lift over

dbSNP: rs770122195; hg19: chrX-123019658;