22-28800538-G-A

Variant names:

• chr22-28800538-G-A
• rs2269575
• NM_001079539.2:c.-14C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001079539.2(XBP1):​c.-14C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0727 in 1,475,272 control chromosomes in the GnomAD database, including 6,027 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.12 (1520 hom., cov: 34)
  • Exomes 𝑓: 0.068 (4507 hom.)
• Consequence: XBP1 NM_001079539.2 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.00
• Publications: 10 publications found

Genes affected

XBP1 (HGNC:12801): (X-box binding protein 1) This gene encodes a transcription factor that regulates MHC class II genes by binding to a promoter element referred to as an X box. This gene product is a bZIP protein, which was also identified as a cellular transcription factor that binds to an enhancer in the promoter of the T cell leukemia virus type 1 promoter. It may increase expression of viral proteins by acting as the DNA binding partner of a viral transactivator. It has been found that upon accumulation of unfolded proteins in the endoplasmic reticulum (ER), the mRNA of this gene is processed to an active form by an unconventional splicing mechanism that is mediated by the endonuclease inositol-requiring enzyme 1 (IRE1). The resulting loss of 26 nt from the spliced mRNA causes a frame-shift and an isoform XBP1(S), which is the functionally active transcription factor. The isoform encoded by the unspliced mRNA, XBP1(U), is constitutively expressed, and thought to function as a negative feedback regulator of XBP1(S), which shuts off transcription of target genes during the recovery phase of ER stress. A pseudogene of XBP1 has been identified and localized to chromosome 5. [provided by RefSeq, Jul 2008]

ENSG00000226471 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.265 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001079539.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XBP1	NM_001079539.2	MANE Select	c.-14C>T		5_prime_UTR	Exon 1 of 6	NP_001073007.1
	XBP1	NM_005080.4		c.-14C>T		5_prime_UTR	Exon 1 of 5	NP_005071.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XBP1	ENST00000344347.6	TSL:5 MANE Select	c.-14C>T		5_prime_UTR	Exon 1 of 6	ENSP00000343155.5
	XBP1	ENST00000216037.10	TSL:1	c.-14C>T		5_prime_UTR	Exon 1 of 5	ENSP00000216037.6
	XBP1	ENST00000482720.1	TSL:2	n.32C>T		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes AF: 0.116 AC: 17696 AN: 152112 Hom.: 1514 Cov.: 34

Gnomad AFR AF: 0.227

Gnomad AMI AF: 0.0537

Gnomad AMR AF: 0.103

Gnomad ASJ AF: 0.0709

Gnomad EAS AF: 0.276

Gnomad SAS AF: 0.0654

Gnomad FIN AF: 0.0726

Gnomad MID AF: 0.0764

Gnomad NFE AF: 0.0542

Gnomad OTH AF: 0.0970

GnomAD2 exomes AF: 0.0885 AC: 6444 AN: 72794 AF XY: 0.0811

Gnomad AFR exome AF: 0.260

Gnomad AMR exome AF: 0.151

Gnomad ASJ exome AF: 0.0703

Gnomad EAS exome AF: 0.281

Gnomad FIN exome AF: 0.0699

Gnomad NFE exome AF: 0.0552

Gnomad OTH exome AF: 0.0763

GnomAD4 exome AF: 0.0676 AC: 89450 AN: 1323052 Hom.: 4507 Cov.: 31 AF XY: 0.0662 AC XY: 43202 AN XY: 652586

African (AFR) AF: 0.232 AC: 6114 AN: 26310

American (AMR) AF: 0.136 AC: 3375 AN: 24824

Ashkenazi Jewish (ASJ) AF: 0.0630 AC: 1441 AN: 22880

East Asian (EAS) AF: 0.302 AC: 8821 AN: 29246

South Asian (SAS) AF: 0.0585 AC: 4263 AN: 72916

European-Finnish (FIN) AF: 0.0609 AC: 2029 AN: 33290

Middle Eastern (MID) AF: 0.0747 AC: 378 AN: 5062

European-Non Finnish (NFE) AF: 0.0555 AC: 58474 AN: 1053596

Other (OTH) AF: 0.0829 AC: 4555 AN: 54928

GnomAD4 genome AF: 0.117 AC: 17742 AN: 152220 Hom.: 1520 Cov.: 34 AF XY: 0.116 AC XY: 8651 AN XY: 74438

African (AFR) AF: 0.227 AC: 9430 AN: 41538

American (AMR) AF: 0.104 AC: 1584 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0709 AC: 246 AN: 3470

East Asian (EAS) AF: 0.277 AC: 1427 AN: 5160

South Asian (SAS) AF: 0.0656 AC: 317 AN: 4830

European-Finnish (FIN) AF: 0.0726 AC: 770 AN: 10608

Middle Eastern (MID) AF: 0.0685 AC: 20 AN: 292

European-Non Finnish (NFE) AF: 0.0542 AC: 3687 AN: 68000

Other (OTH) AF: 0.100 AC: 212 AN: 2114

Alfa AF: 0.0285 Hom.: 21

Bravo AF: 0.126

Asia WGS AF: 0.186 AC: 642 AN: 3468

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	9.1
DANN	Benign	0.65
PhyloP100		0.0
PromoterAI		-0.10	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Mutation Taster		=300/0	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: rs2269575; hg19: chr22-29196526; COSMIC: COSV107235241; COSMIC: COSV107235241;