rs35873774

Positions:

• chr22-28795944-A-G

Variant summary

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

The NM_001079539.2(XBP1):​c.573+103T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0549 in 1,504,106 control chromosomes in the GnomAD database, including 2,629 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 0.045 (204 hom., cov: 32)
  • Exomes 𝑓: 0.056 (2425 hom.)
• Consequence: XBP1 NM_001079539.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.09

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=-0.84).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0636 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
XBP1	NM_001079539.2	c.573+103T>C		intron_variant		ENST00000344347.6
XBP1	NM_001393999.1	c.423+103T>C		intron_variant
XBP1	NM_001394000.1	c.449+103T>C		intron_variant
XBP1	NM_005080.4	c.599+103T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
XBP1	ENST00000344347.6	c.573+103T>C		intron_variant		5	NM_001079539.2	P4

Frequencies

GnomAD3 genomes AF: 0.0450 AC: 6848 AN: 152172 Hom.: 204 Cov.: 32

Gnomad AFR AF: 0.0205

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0256

Gnomad ASJ AF: 0.0182

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0304

Gnomad FIN AF: 0.0851

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0652

Gnomad OTH AF: 0.0282

GnomAD4 exome AF: 0.0560 AC: 75662 AN: 1351816 Hom.: 2425 AF XY: 0.0552 AC XY: 37329 AN XY: 676270

Gnomad4 AFR exome AF: 0.0189

Gnomad4 AMR exome AF: 0.0187

Gnomad4 ASJ exome AF: 0.0126

Gnomad4 EAS exome AF: 0.000153

Gnomad4 SAS exome AF: 0.0258

Gnomad4 FIN exome AF: 0.0822

Gnomad4 NFE exome AF: 0.0636

Gnomad4 OTH exome AF: 0.0465

GnomAD4 genome AF: 0.0450 AC: 6847 AN: 152290 Hom.: 204 Cov.: 32 AF XY: 0.0450 AC XY: 3354 AN XY: 74466

Gnomad4 AFR AF: 0.0204

Gnomad4 AMR AF: 0.0256

Gnomad4 ASJ AF: 0.0182

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0310

Gnomad4 FIN AF: 0.0851

Gnomad4 NFE AF: 0.0652

Gnomad4 OTH AF: 0.0279

Alfa AF: 0.0594 Hom.: 44

Bravo AF: 0.0383

Asia WGS AF: 0.0110 AC: 38 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	8.9
DANN	Benign	0.65
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs35873774; hg19: chr22-29191932;