22-28796682-T-C

Variant names:

• chr22-28796682-T-C
• rs2239815
• NM_001079539.2:c.453+395A>G

Variant summary

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

The NM_001079539.2(XBP1):​c.453+395A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.425 in 173,466 control chromosomes in the GnomAD database, including 18,353 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 0.44 (16996 hom., cov: 32)
  • Exomes 𝑓: 0.33 (1357 hom.)
• Consequence: XBP1 NM_001079539.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0440
• Publications: 46 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=-0.85).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.684 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.453+395A>G		intron	N/A	NP_001073007.1	P17861-2
	XBP1	NM_001393999.1		c.303+395A>G		intron	N/A	NP_001380928.1
	XBP1	NM_005080.4		c.453+395A>G		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.453+395A>G		intron	N/A	ENSP00000343155.5	P17861-2
	XBP1	ENST00000216037.10	TSL:1	c.453+395A>G		intron	N/A	ENSP00000216037.6	P17861-1
	XBP1	ENST00000933819.1		c.453+395A>G		intron	N/A	ENSP00000603878.1

Frequencies

GnomAD3 genomes AF: 0.438 AC: 66503 AN: 151744 Hom.: 16944 Cov.: 32

Gnomad AFR AF: 0.690

Gnomad AMI AF: 0.186

Gnomad AMR AF: 0.315

Gnomad ASJ AF: 0.333

Gnomad EAS AF: 0.678

Gnomad SAS AF: 0.537

Gnomad FIN AF: 0.373

Gnomad MID AF: 0.365

Gnomad NFE AF: 0.308

Gnomad OTH AF: 0.402

GnomAD4 exome AF: 0.326 AC: 7034 AN: 21600 Hom.: 1357 Cov.: 0 AF XY: 0.332 AC XY: 3697 AN XY: 11128

African (AFR) AF: 0.690 AC: 280 AN: 406

American (AMR) AF: 0.317 AC: 447 AN: 1410

Ashkenazi Jewish (ASJ) AF: 0.275 AC: 157 AN: 570

East Asian (EAS) AF: 0.662 AC: 368 AN: 556

South Asian (SAS) AF: 0.471 AC: 790 AN: 1678

European-Finnish (FIN) AF: 0.370 AC: 346 AN: 934

Middle Eastern (MID) AF: 0.325 AC: 26 AN: 80

European-Non Finnish (NFE) AF: 0.285 AC: 4165 AN: 14612

Other (OTH) AF: 0.336 AC: 455 AN: 1354

GnomAD4 genome AF: 0.439 AC: 66619 AN: 151866 Hom.: 16996 Cov.: 32 AF XY: 0.440 AC XY: 32646 AN XY: 74178

African (AFR) AF: 0.691 AC: 28601 AN: 41406

American (AMR) AF: 0.316 AC: 4820 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.333 AC: 1155 AN: 3472

East Asian (EAS) AF: 0.678 AC: 3481 AN: 5136

South Asian (SAS) AF: 0.536 AC: 2575 AN: 4804

European-Finnish (FIN) AF: 0.373 AC: 3918 AN: 10518

Middle Eastern (MID) AF: 0.363 AC: 106 AN: 292

European-Non Finnish (NFE) AF: 0.308 AC: 20938 AN: 67946

Other (OTH) AF: 0.406 AC: 856 AN: 2108

Alfa AF: 0.350 Hom.: 30658

Bravo AF: 0.442

Asia WGS AF: 0.619 AC: 2151 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	3.3
DANN	Benign	0.78
PhyloP100		-0.044
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: rs2239815; hg19: chr22-29192670;