22-28794483-T-C

Variant names:

• chr22-28794483-T-C
• rs2267131
• NM_001079539.2:c.*692A>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.*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
• Publications: 11 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 (SAS) allele frequency at 95% confidence interval = 0.268 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.*692A>G		downstream_gene	N/A	NP_001073007.1	P17861-2
	XBP1	NM_001393999.1		c.*692A>G		downstream_gene	N/A	NP_001380928.1
	XBP1	NM_005080.4		c.*1063A>G		downstream_gene	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.*692A>G		downstream_gene	N/A	ENSP00000343155.5	P17861-2
	XBP1	ENST00000216037.10	TSL:1	c.*1063A>G		downstream_gene	N/A	ENSP00000216037.6	P17861-1
	XBP1	ENST00000933819.1		c.*692A>G		downstream_gene	N/A	ENSP00000603878.1

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

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.172 AC: 23 AN: 134

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2

European-Non Finnish (NFE) AF: 0.125 AC: 1 AN: 8

Other (OTH) AC: 0 AN: 0

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

African (AFR) AF: 0.0658 AC: 2735 AN: 41554

American (AMR) AF: 0.0850 AC: 1300 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.130 AC: 452 AN: 3470

East Asian (EAS) AF: 0.205 AC: 1065 AN: 5186

South Asian (SAS) AF: 0.280 AC: 1353 AN: 4826

European-Finnish (FIN) AF: 0.101 AC: 1073 AN: 10612

Middle Eastern (MID) AF: 0.211 AC: 62 AN: 294

European-Non Finnish (NFE) AF: 0.133 AC: 9065 AN: 68012

Other (OTH) AF: 0.138 AC: 292 AN: 2112

Alfa AF: 0.119 Hom.: 558

Bravo AF: 0.110

Asia WGS AF: 0.239 AC: 834 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	1.5
DANN	Benign	0.42
PhyloP100		0.051

Splicing

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

Other links and lift over

dbSNP: rs2267131; hg19: chr22-29190471;