rs28382742

Variant names:

• chrX-123907984-G-T
• rs28382742
• NM_001167.4:c.*803G>T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001167.4(XIAP):​c.*803G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (1440 hom., 3849 hem., cov: 20)
  • Exomes 𝑓: 0.21 (3898 hom. 21810 hem.)
• Consequence: XIAP NM_001167.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.392

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant X-123907984-G-T is Benign according to our data. Variant chrX-123907984-G-T is described in ClinVar as [Benign]. Clinvar id is 367801.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.297 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XIAP	NM_001167.4	c.*803G>T		3_prime_UTR_variant	Exon 7 of 7	ENST00000371199.8	NP_001158.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XIAP	ENST00000371199.8	c.*803G>T		3_prime_UTR_variant	Exon 7 of 7	1	NM_001167.4	ENSP00000360242.3
XIAP	ENST00000355640.3	c.*803G>T		3_prime_UTR_variant	Exon 7 of 7	5		ENSP00000347858.3
XIAP	ENST00000422098.6	c.*803G>T		3_prime_UTR_variant	Exon 9 of 9	4		ENSP00000405529.2

Frequencies

GnomAD3 genomes AF: 0.172 AC: 18263 AN: 106197 Hom.: 1442 Cov.: 20 AF XY: 0.131 AC XY: 3843 AN XY: 29365

Gnomad AFR AF: 0.126

Gnomad AMI AF: 0.150

Gnomad AMR AF: 0.185

Gnomad ASJ AF: 0.181

Gnomad EAS AF: 0.296

Gnomad SAS AF: 0.317

Gnomad FIN AF: 0.174

Gnomad MID AF: 0.279

Gnomad NFE AF: 0.180

Gnomad OTH AF: 0.180

GnomAD3 exomes AF: 0.237 AC: 20842 AN: 88057 Hom.: 1809 AF XY: 0.242 AC XY: 7495 AN XY: 30911

Gnomad AFR exome AF: 0.142

Gnomad AMR exome AF: 0.203

Gnomad ASJ exome AF: 0.196

Gnomad EAS exome AF: 0.367

Gnomad SAS exome AF: 0.387

Gnomad FIN exome AF: 0.246

Gnomad NFE exome AF: 0.191

Gnomad OTH exome AF: 0.225

GnomAD4 exome AF: 0.211 AC: 52911 AN: 250214 Hom.: 3898 Cov.: 0 AF XY: 0.234 AC XY: 21810 AN XY: 93330

Gnomad4 AFR exome AF: 0.121

Gnomad4 AMR exome AF: 0.198

Gnomad4 ASJ exome AF: 0.170

Gnomad4 EAS exome AF: 0.268

Gnomad4 SAS exome AF: 0.384

Gnomad4 FIN exome AF: 0.244

Gnomad4 NFE exome AF: 0.174

Gnomad4 OTH exome AF: 0.189

GnomAD4 genome AF: 0.172 AC: 18259 AN: 106228 Hom.: 1440 Cov.: 20 AF XY: 0.131 AC XY: 3849 AN XY: 29412

Gnomad4 AFR AF: 0.126

Gnomad4 AMR AF: 0.185

Gnomad4 ASJ AF: 0.181

Gnomad4 EAS AF: 0.296

Gnomad4 SAS AF: 0.316

Gnomad4 FIN AF: 0.174

Gnomad4 NFE AF: 0.180

Gnomad4 OTH AF: 0.186

Alfa AF: 0.194 Hom.: 1689

Bravo AF: 0.191

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

X-linked lymphoproliferative disease due to XIAP deficiency Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.42
DANN	Benign	0.52
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs28382742; hg19: chrX-123041834;