rs2097461

Variant names:

• chr22-28795891-T-C
• rs2097461
• ENST00000344347.6:c.573+156A>G

Variant summary

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

The ENST00000344347.6(XBP1):​c.573+156A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.397 in 152,006 control chromosomes in the GnomAD database, including 13,236 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 0.40 (13236 hom., cov: 32)
• Consequence: XBP1 ENST00000344347.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.538
• Publications: 17 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]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.647 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XBP1	NM_001079539.2	c.573+156A>G		intron_variant	Intron 5 of 5		NP_001073007.1
XBP1	NM_001393999.1	c.423+156A>G		intron_variant	Intron 5 of 5		NP_001380928.1
XBP1	NM_005080.4	c.599+156A>G		intron_variant	Intron 4 of 4		NP_005071.2
XBP1	NM_001394000.1	c.449+156A>G		intron_variant	Intron 4 of 4		NP_001380929.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XBP1	ENST00000344347.6	c.573+156A>G		intron_variant	Intron 5 of 5	5		ENSP00000343155.5

Frequencies

GnomAD3 genomes AF: 0.397 AC: 60255 AN: 151888 Hom.: 13208 Cov.: 32

Gnomad AFR AF: 0.549

Gnomad AMI AF: 0.185

Gnomad AMR AF: 0.295

Gnomad ASJ AF: 0.331

Gnomad EAS AF: 0.666

Gnomad SAS AF: 0.536

Gnomad FIN AF: 0.372

Gnomad MID AF: 0.339

Gnomad NFE AF: 0.307

Gnomad OTH AF: 0.368

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.397 AC: 60339 AN: 152006 Hom.: 13236 Cov.: 32 AF XY: 0.400 AC XY: 29737 AN XY: 74294

African (AFR) AF: 0.550 AC: 22774 AN: 41440

American (AMR) AF: 0.296 AC: 4520 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.331 AC: 1147 AN: 3468

East Asian (EAS) AF: 0.666 AC: 3446 AN: 5176

South Asian (SAS) AF: 0.535 AC: 2573 AN: 4812

European-Finnish (FIN) AF: 0.372 AC: 3930 AN: 10560

Middle Eastern (MID) AF: 0.340 AC: 100 AN: 294

European-Non Finnish (NFE) AF: 0.307 AC: 20895 AN: 67970

Other (OTH) AF: 0.373 AC: 786 AN: 2108

Alfa AF: 0.338 Hom.: 5318

Bravo AF: 0.395

Asia WGS AF: 0.603 AC: 2097 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.3
DANN	Benign	0.60
PhyloP100		-0.54
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: rs2097461; hg19: chr22-29191879; COSMIC: COSV53274368; COSMIC: COSV53274368;