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: Labcorp Genetics (formerly Invitae), Orphanet

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001167.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XIAP	NM_001167.4	MANE Select	c.*12A>G		3_prime_UTR	Exon 7 of 7	NP_001158.2
	XIAP	NM_001204401.2		c.*12A>G		3_prime_UTR	Exon 7 of 7	NP_001191330.1	P98170
	XIAP	NM_001378590.1		c.*12A>G		3_prime_UTR	Exon 7 of 7	NP_001365519.1	P98170

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XIAP	ENST00000371199.8	TSL:1 MANE Select	c.*12A>G		3_prime_UTR	Exon 7 of 7	ENSP00000360242.3	P98170
	XIAP	ENST00000355640.3	TSL:5	c.*12A>G		3_prime_UTR	Exon 7 of 7	ENSP00000347858.3	P98170
	XIAP	ENST00000422098.6	TSL:4	c.*12A>G		3_prime_UTR	Exon 9 of 9	ENSP00000405529.2	P98170

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	X-linked lymphoproliferative disease due to XIAP deficiency (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

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;