22-28796682-T-C

Variant names:

• chr22-28796682-T-C
• rs2239815
• ENST00000344347.6:c.453+395A>G

Variant summary

Our verdict is Benign. Variant got -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

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=-0.85).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.684 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XBP1	NM_001079539.2	c.453+395A>G		intron_variant	Intron 3 of 5		NP_001073007.1
XBP1	NM_001393999.1	c.303+395A>G		intron_variant	Intron 3 of 5		NP_001380928.1
XBP1	NM_005080.4	c.453+395A>G		intron_variant	Intron 3 of 4		NP_005071.2
XBP1	NM_001394000.1	c.303+395A>G		intron_variant	Intron 3 of 4		NP_001380929.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XBP1	ENST00000344347.6	c.453+395A>G		intron_variant	Intron 3 of 5	5		ENSP00000343155.5

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

Gnomad4 AFR exome AF: 0.690

Gnomad4 AMR exome AF: 0.317

Gnomad4 ASJ exome AF: 0.275

Gnomad4 EAS exome AF: 0.662

Gnomad4 SAS exome AF: 0.471

Gnomad4 FIN exome AF: 0.370

Gnomad4 NFE exome AF: 0.285

Gnomad4 OTH exome AF: 0.336

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

Gnomad4 AFR AF: 0.691

Gnomad4 AMR AF: 0.316

Gnomad4 ASJ AF: 0.333

Gnomad4 EAS AF: 0.678

Gnomad4 SAS AF: 0.536

Gnomad4 FIN AF: 0.373

Gnomad4 NFE AF: 0.308

Gnomad4 OTH AF: 0.406

Alfa AF: 0.319 Hom.: 9159

Bravo AF: 0.442

Asia WGS AF: 0.619 AC: 2151 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	3.3
DANN	Benign	0.78

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: rs2239815; hg19: chr22-29192670;