X-123907261-G-C

Variant names:

• chrX-123907261-G-C
• rs12838858
• NM_001167.4:c.*80G>C

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.*80G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0849 in 915,101 control chromosomes in the GnomAD database, including 2,669 homozygotes. There are 21,564 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.060 (213 hom., 1974 hem., cov: 23)
  • Exomes 𝑓: 0.088 (2456 hom. 19590 hem.)
• Consequence: XIAP NM_001167.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0530

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=-0.82).
• BP6: Variant X-123907261-G-C is Benign according to our data. Variant chrX-123907261-G-C is described in ClinVar as [Benign]. Clinvar id is 367797.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0909 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XIAP	NM_001167.4	c.*80G>C		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.*80G>C		3_prime_UTR_variant	Exon 7 of 7	1	NM_001167.4	ENSP00000360242.3

Frequencies

GnomAD3 genomes AF: 0.0605 AC: 6748 AN: 111529 Hom.: 213 Cov.: 23 AF XY: 0.0585 AC XY: 1974 AN XY: 33745

Gnomad AFR AF: 0.0138

Gnomad AMI AF: 0.00878

Gnomad AMR AF: 0.0458

Gnomad ASJ AF: 0.0557

Gnomad EAS AF: 0.000559

Gnomad SAS AF: 0.0335

Gnomad FIN AF: 0.0981

Gnomad MID AF: 0.0336

Gnomad NFE AF: 0.0930

Gnomad OTH AF: 0.0514

GnomAD3 exomes AF: 0.0637 AC: 8444 AN: 132506 Hom.: 232 AF XY: 0.0645 AC XY: 2656 AN XY: 41164

Gnomad AFR exome AF: 0.0121

Gnomad AMR exome AF: 0.0295

Gnomad ASJ exome AF: 0.0504

Gnomad EAS exome AF: 0.000199

Gnomad SAS exome AF: 0.0481

Gnomad FIN exome AF: 0.106

Gnomad NFE exome AF: 0.0941

Gnomad OTH exome AF: 0.0597

GnomAD4 exome AF: 0.0883 AC: 70937 AN: 803518 Hom.: 2456 Cov.: 14 AF XY: 0.0922 AC XY: 19590 AN XY: 212424

Gnomad4 AFR exome AF: 0.0139

Gnomad4 AMR exome AF: 0.0299

Gnomad4 ASJ exome AF: 0.0515

Gnomad4 EAS exome AF: 0.000584

Gnomad4 SAS exome AF: 0.0499

Gnomad4 FIN exome AF: 0.109

Gnomad4 NFE exome AF: 0.101

Gnomad4 OTH exome AF: 0.0772

GnomAD4 genome AF: 0.0605 AC: 6749 AN: 111583 Hom.: 213 Cov.: 23 AF XY: 0.0584 AC XY: 1974 AN XY: 33809

Gnomad4 AFR AF: 0.0138

Gnomad4 AMR AF: 0.0457

Gnomad4 ASJ AF: 0.0557

Gnomad4 EAS AF: 0.000560

Gnomad4 SAS AF: 0.0333

Gnomad4 FIN AF: 0.0981

Gnomad4 NFE AF: 0.0930

Gnomad4 OTH AF: 0.0514

Alfa AF: 0.0417 Hom.: 301

Bravo AF: 0.0551

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	-0.82
CADD	Benign	7.7
DANN	Benign	0.79

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: rs12838858; hg19: chrX-123041111;