rs35873774

Variant names:

• chr22-28795944-A-G
• rs35873774
• NM_001079539.2: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
• Publications: 20 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=-0.84).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0636 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XBP1	NM_001079539.2	MANE Select	c.573+103T>C		intron	N/A	NP_001073007.1	P17861-2
	XBP1	NM_001393999.1		c.423+103T>C		intron	N/A	NP_001380928.1
	XBP1	NM_005080.4		c.599+103T>C		intron	N/A	NP_005071.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XBP1	ENST00000344347.6	TSL:5 MANE Select	c.573+103T>C		intron	N/A	ENSP00000343155.5	P17861-2
	XBP1	ENST00000216037.10	TSL:1	c.599+103T>C		intron	N/A	ENSP00000216037.6	P17861-1
	XBP1	ENST00000933819.1		c.454-212T>C		intron	N/A	ENSP00000603878.1

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

African (AFR) AF: 0.0189 AC: 592 AN: 31348

American (AMR) AF: 0.0187 AC: 791 AN: 42370

Ashkenazi Jewish (ASJ) AF: 0.0126 AC: 304 AN: 24092

East Asian (EAS) AF: 0.000153 AC: 6 AN: 39166

South Asian (SAS) AF: 0.0258 AC: 2073 AN: 80470

European-Finnish (FIN) AF: 0.0822 AC: 3990 AN: 48566

Middle Eastern (MID) AF: 0.0173 AC: 87 AN: 5032

European-Non Finnish (NFE) AF: 0.0636 AC: 65181 AN: 1024094

Other (OTH) 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

African (AFR) AF: 0.0204 AC: 846 AN: 41572

American (AMR) AF: 0.0256 AC: 391 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0182 AC: 63 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.0310 AC: 150 AN: 4832

European-Finnish (FIN) AF: 0.0851 AC: 903 AN: 10610

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0652 AC: 4431 AN: 68008

Other (OTH) AF: 0.0279 AC: 59 AN: 2114

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	8.9
DANN	Benign	0.65
PhyloP100		2.1
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

Other links and lift over

dbSNP: rs35873774; hg19: chr22-29191932;