chrX-123910026-C-T

Variant names:

• chrX-123910026-C-T
• rs17330644
• NM_001167.4:c.*2845C>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.*2845C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.223 in 326,921 control chromosomes in the GnomAD database, including 5,175 homozygotes. There are 28,723 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (1513 hom., 6692 hem., cov: 23)
  • Exomes 𝑓: 0.24 (3662 hom. 22031 hem.)
• Consequence: XIAP NM_001167.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.234

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=-0.85).
• BP6: Variant X-123910026-C-T is Benign according to our data. Variant chrX-123910026-C-T is described in ClinVar as [Benign]. Clinvar id is 367816.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.367 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XIAP	NM_001167.4	c.*2845C>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.*2845C>T		3_prime_UTR_variant	Exon 7 of 7	1	NM_001167.4	ENSP00000360242.3
XIAP	ENST00000355640.3	c.*2845C>T		3_prime_UTR_variant	Exon 7 of 7	5		ENSP00000347858.3

Frequencies

GnomAD3 genomes AF: 0.196 AC: 21758 AN: 111056 Hom.: 1513 Cov.: 23 AF XY: 0.201 AC XY: 6681 AN XY: 33272

Gnomad AFR AF: 0.149

Gnomad AMI AF: 0.169

Gnomad AMR AF: 0.223

Gnomad ASJ AF: 0.189

Gnomad EAS AF: 0.332

Gnomad SAS AF: 0.387

Gnomad FIN AF: 0.258

Gnomad MID AF: 0.315

Gnomad NFE AF: 0.192

Gnomad OTH AF: 0.197

GnomAD3 exomes AF: 0.242 AC: 23854 AN: 98475 Hom.: 1927 AF XY: 0.253 AC XY: 9186 AN XY: 36281

Gnomad AFR exome AF: 0.155

Gnomad AMR exome AF: 0.212

Gnomad ASJ exome AF: 0.204

Gnomad EAS exome AF: 0.373

Gnomad SAS exome AF: 0.392

Gnomad FIN exome AF: 0.249

Gnomad NFE exome AF: 0.196

Gnomad OTH exome AF: 0.230

GnomAD4 exome AF: 0.237 AC: 51080 AN: 215811 Hom.: 3662 Cov.: 0 AF XY: 0.257 AC XY: 22031 AN XY: 85871

Gnomad4 AFR exome AF: 0.154

Gnomad4 AMR exome AF: 0.211

Gnomad4 ASJ exome AF: 0.203

Gnomad4 EAS exome AF: 0.363

Gnomad4 SAS exome AF: 0.387

Gnomad4 FIN exome AF: 0.244

Gnomad4 NFE exome AF: 0.195

Gnomad4 OTH exome AF: 0.226

GnomAD4 genome AF: 0.196 AC: 21764 AN: 111110 Hom.: 1513 Cov.: 23 AF XY: 0.201 AC XY: 6692 AN XY: 33336

Gnomad4 AFR AF: 0.149

Gnomad4 AMR AF: 0.222

Gnomad4 ASJ AF: 0.189

Gnomad4 EAS AF: 0.333

Gnomad4 SAS AF: 0.387

Gnomad4 FIN AF: 0.258

Gnomad4 NFE AF: 0.192

Gnomad4 OTH AF: 0.203

Alfa AF: 0.192 Hom.: 7223

Bravo AF: 0.193

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	-0.85
CADD	Benign	7.5
DANN	Benign	0.34

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: rs17330644; hg19: chrX-123043876;