rs35873774

Variant names:

• chr22-28795944-A-G
• rs35873774
• ENST00000344347.6:c.573+103T>C

Variant summary

Our verdict is Benign. The variant received -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

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
XBP1	NM_001079539.2	c.573+103T>C		intron_variant	Intron 5 of 5		NP_001073007.1
XBP1	NM_001393999.1	c.423+103T>C		intron_variant	Intron 5 of 5		NP_001380928.1
XBP1	NM_005080.4	c.599+103T>C		intron_variant	Intron 4 of 4		NP_005071.2
XBP1	NM_001394000.1	c.449+103T>C		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+103T>C		intron_variant	Intron 5 of 5	5		ENSP00000343155.5

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 AC: 592 AN: 31348

Gnomad4 AMR exome AF: 0.0187 AC: 791 AN: 42370

Gnomad4 ASJ exome AF: 0.0126 AC: 304 AN: 24092

Gnomad4 EAS exome AF: 0.000153 AC: 6 AN: 39166

Gnomad4 SAS exome AF: 0.0258 AC: 2073 AN: 80470

Gnomad4 FIN exome AF: 0.0822 AC: 3990 AN: 48566

Gnomad4 NFE exome AF: 0.0636 AC: 65181 AN: 1024094

Gnomad4 Remaining exome AF: 0.0465 AC: 2638 AN: 56678

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 AC: 0.0203502 AN: 0.0203502

Gnomad4 AMR AF: 0.0256 AC: 0.0255589 AN: 0.0255589

Gnomad4 ASJ AF: 0.0182 AC: 0.0181556 AN: 0.0181556

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.0310 AC: 0.031043 AN: 0.031043

Gnomad4 FIN AF: 0.0851 AC: 0.0851084 AN: 0.0851084

Gnomad4 NFE AF: 0.0652 AC: 0.0651541 AN: 0.0651541

Gnomad4 OTH AF: 0.0279 AC: 0.0279092 AN: 0.0279092

Alfa AF: 0.0508 Hom.: 71

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
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

Publications

LitVar

Other links and lift over

dbSNP: rs35873774; hg19: chr22-29191932;