22-28794483-T-C

Variant names:

• chr22-28794483-T-C
• rs2267131
• ENST00000344347.6:c.*692A>G

Variant summary

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

The NM_001079539.2(XBP1):​c.*692A>G variant causes a downstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.115 in 152,420 control chromosomes in the GnomAD database, including 1,183 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 0.11 (1181 hom., cov: 32)
  • Exomes 𝑓: 0.17 (2 hom.)
• Consequence: XBP1 NM_001079539.2 downstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0510

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 (SAS) allele frequency at 95% confidence interval = 0.268 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XBP1	NM_001079539.2	c.*692A>G		downstream_gene_variant			NP_001073007.1
XBP1	NM_001393999.1	c.*692A>G		downstream_gene_variant			NP_001380928.1
XBP1	NM_005080.4	c.*1063A>G		downstream_gene_variant			NP_005071.2
XBP1	NM_001394000.1	c.*1063A>G		downstream_gene_variant			NP_001380929.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XBP1	ENST00000344347.6	c.*692A>G		downstream_gene_variant		5		ENSP00000343155.5

Frequencies

GnomAD3 genomes AF: 0.115 AC: 17487 AN: 152158 Hom.: 1183 Cov.: 32

Gnomad AFR AF: 0.0660

Gnomad AMI AF: 0.0910

Gnomad AMR AF: 0.0851

Gnomad ASJ AF: 0.130

Gnomad EAS AF: 0.206

Gnomad SAS AF: 0.281

Gnomad FIN AF: 0.101

Gnomad MID AF: 0.203

Gnomad NFE AF: 0.133

Gnomad OTH AF: 0.139

GnomAD4 exome AF: 0.167 AC: 24 AN: 144 Hom.: 2 AF XY: 0.176 AC XY: 13 AN XY: 74

Gnomad4 EAS exome AF: 0.172

Gnomad4 NFE exome AF: 0.125

GnomAD4 genome AF: 0.115 AC: 17480 AN: 152276 Hom.: 1181 Cov.: 32 AF XY: 0.116 AC XY: 8603 AN XY: 74464

Gnomad4 AFR AF: 0.0658

Gnomad4 AMR AF: 0.0850

Gnomad4 ASJ AF: 0.130

Gnomad4 EAS AF: 0.205

Gnomad4 SAS AF: 0.280

Gnomad4 FIN AF: 0.101

Gnomad4 NFE AF: 0.133

Gnomad4 OTH AF: 0.138

Alfa AF: 0.119 Hom.: 467

Bravo AF: 0.110

Asia WGS AF: 0.239 AC: 834 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	1.5
DANN	Benign	0.42

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2267131; hg19: chr22-29190471;