rs2097461

chr22-28795891-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001079539.2(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 NM_001079539.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.538

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

Verdict is Benign. Variant got -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/exons	MANE	UniProt
XBP1	NM_001079539.2	c.573+156A>G		intron_variant		ENST00000344347.6
XBP1	NM_001393999.1	c.423+156A>G		intron_variant
XBP1	NM_001394000.1	c.449+156A>G		intron_variant
XBP1	NM_005080.4	c.599+156A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
XBP1	ENST00000344347.6	c.573+156A>G		intron_variant		5	NM_001079539.2	P4

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

Gnomad4 AFR AF: 0.550

Gnomad4 AMR AF: 0.296

Gnomad4 ASJ AF: 0.331

Gnomad4 EAS AF: 0.666

Gnomad4 SAS AF: 0.535

Gnomad4 FIN AF: 0.372

Gnomad4 NFE AF: 0.307

Gnomad4 OTH AF: 0.373

Alfa AF: 0.335 Hom.: 3480

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

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: rs2097461; hg19: chr22-29191879; COSMIC: COSV53274368; COSMIC: COSV53274368;