chrX-123907984-G-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 3 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 -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 VariationId 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
XIAP	ENST00000698505.1	n.*126G>T		downstream_gene_variant

Frequencies

GnomAD3 genomes AF: 0.172 AC: 18263 AN: 106197 Hom.: 1442 Cov.: 20

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

GnomAD2 exomes AF: 0.237 AC: 20842 AN: 88057 AF XY: 0.242

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 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

African (AFR) AF: 0.121 AC: 1022 AN: 8476

American (AMR) AF: 0.198 AC: 4289 AN: 21696

Ashkenazi Jewish (ASJ) AF: 0.170 AC: 1702 AN: 9996

East Asian (EAS) AF: 0.268 AC: 3326 AN: 12410

South Asian (SAS) AF: 0.384 AC: 13363 AN: 34796

European-Finnish (FIN) AF: 0.244 AC: 2277 AN: 9330

Middle Eastern (MID) AF: 0.248 AC: 245 AN: 986

European-Non Finnish (NFE) AF: 0.174 AC: 24139 AN: 139012

Other (OTH) AF: 0.189 AC: 2548 AN: 13512

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

African (AFR) AF: 0.126 AC: 3712 AN: 29453

American (AMR) AF: 0.185 AC: 1781 AN: 9640

Ashkenazi Jewish (ASJ) AF: 0.181 AC: 468 AN: 2582

East Asian (EAS) AF: 0.296 AC: 963 AN: 3248

South Asian (SAS) AF: 0.316 AC: 710 AN: 2245

European-Finnish (FIN) AF: 0.174 AC: 888 AN: 5090

Middle Eastern (MID) AF: 0.278 AC: 57 AN: 205

European-Non Finnish (NFE) AF: 0.180 AC: 9313 AN: 51665

Other (OTH) AF: 0.186 AC: 268 AN: 1442

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
PhyloP100		-0.39
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs28382742; hg19: chrX-123041834;