rs28382740

Variant names:

• chrX-123907193-A-G
• rs28382740
• NM_001167.4:c.*12A>G

Your query was ambiguous. Multiple possible variants found:

• chrX-123907193-A-G
• chrX-123907193-A-T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001167.4(XIAP):​c.*12A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.21 in 1,177,667 control chromosomes in the GnomAD database, including 18,019 homozygotes. There are 81,282 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 (1528 hom., 6631 hem., cov: 23)
  • Exomes 𝑓: 0.21 (16491 hom. 74651 hem.)
• Consequence: XIAP NM_001167.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.402
• Publications: 20 publications found

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]

XIAP Gene-Disease associations (from GenCC):

• X-linked lymphoproliferative disease due to XIAP deficiency

  Inheritance: XL Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP6: Variant X-123907193-A-G is Benign according to our data. Variant chrX-123907193-A-G is described in ClinVar as Benign. ClinVar VariationId is 367796.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.362 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XIAP	NM_001167.4	c.*12A>G		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.*12A>G		3_prime_UTR_variant	Exon 7 of 7	1	NM_001167.4	ENSP00000360242.3

Frequencies

GnomAD3 genomes AF: 0.197 AC: 21837 AN: 111098 Hom.: 1528 Cov.: 23

Gnomad AFR AF: 0.155

Gnomad AMI AF: 0.163

Gnomad AMR AF: 0.221

Gnomad ASJ AF: 0.188

Gnomad EAS AF: 0.336

Gnomad SAS AF: 0.381

Gnomad FIN AF: 0.252

Gnomad MID AF: 0.314

Gnomad NFE AF: 0.192

Gnomad OTH AF: 0.200

GnomAD2 exomes AF: 0.234 AC: 41172 AN: 175709 AF XY: 0.243

Gnomad AFR exome AF: 0.160

Gnomad AMR exome AF: 0.209

Gnomad ASJ exome AF: 0.203

Gnomad EAS exome AF: 0.367

Gnomad FIN exome AF: 0.244

Gnomad NFE exome AF: 0.195

Gnomad OTH exome AF: 0.228

GnomAD4 exome AF: 0.211 AC: 225216 AN: 1066516 Hom.: 16491 Cov.: 27 AF XY: 0.222 AC XY: 74651 AN XY: 335710

African (AFR) AF: 0.160 AC: 4123 AN: 25807

American (AMR) AF: 0.216 AC: 7507 AN: 34816

Ashkenazi Jewish (ASJ) AF: 0.199 AC: 3816 AN: 19158

East Asian (EAS) AF: 0.307 AC: 9217 AN: 30024

South Asian (SAS) AF: 0.392 AC: 20870 AN: 53194

European-Finnish (FIN) AF: 0.243 AC: 9795 AN: 40386

Middle Eastern (MID) AF: 0.297 AC: 1200 AN: 4037

European-Non Finnish (NFE) AF: 0.195 AC: 158822 AN: 814034

Other (OTH) AF: 0.219 AC: 9866 AN: 45060

GnomAD4 genome AF: 0.197 AC: 21844 AN: 111151 Hom.: 1528 Cov.: 23 AF XY: 0.199 AC XY: 6631 AN XY: 33381

African (AFR) AF: 0.154 AC: 4742 AN: 30707

American (AMR) AF: 0.221 AC: 2292 AN: 10383

Ashkenazi Jewish (ASJ) AF: 0.188 AC: 497 AN: 2639

East Asian (EAS) AF: 0.336 AC: 1177 AN: 3499

South Asian (SAS) AF: 0.381 AC: 1015 AN: 2662

European-Finnish (FIN) AF: 0.252 AC: 1488 AN: 5914

Middle Eastern (MID) AF: 0.312 AC: 67 AN: 215

European-Non Finnish (NFE) AF: 0.192 AC: 10144 AN: 52944

Other (OTH) AF: 0.206 AC: 312 AN: 1512

Alfa AF: 0.193 Hom.: 1668

Bravo AF: 0.195

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Nov 12, 2023

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 36% of patients studied by a panel of primary immunodeficiencies. Number of patients: 35. Only high quality variants are reported. -

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Mar 22, 2018

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	12
DANN	Benign	0.73
PhyloP100		0.40
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.24		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs28382740; hg19: chrX-123041043; COSMIC: COSV63022434; COSMIC: COSV63022434;