22-28800510-T-TGCCG

Variant names:

• chr22-28800510-T-TGCCG
• rs528996789
• ENST00000344347.6:c.14_15insCGGC

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001079539.2(XBP1):​c.14_15insCGGC​(p.Ala6GlyfsTer12) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: XBP1 NM_001079539.2 frameshift
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.69

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XBP1	NM_001079539.2	c.14_15insCGGC	p.Ala6GlyfsTer12	frameshift_variant	Exon 1 of 6		NP_001073007.1
XBP1	NM_005080.4	c.14_15insCGGC	p.Ala6GlyfsTer12	frameshift_variant	Exon 1 of 5		NP_005071.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XBP1	ENST00000344347.6	c.14_15insCGGC	p.Ala6GlyfsTer12	frameshift_variant	Exon 1 of 6	5		ENSP00000343155.5
XBP1	ENST00000216037.10	c.14_15insCGGC	p.Ala6GlyfsTer12	frameshift_variant	Exon 1 of 5	1		ENSP00000216037.6
XBP1	ENST00000403532.7	c.14_15insCGGC	p.Ala6GlyfsTer12	frameshift_variant	Exon 1 of 5	3		ENSP00000385162.3
XBP1	ENST00000482720.1	n.59_60insCGGC		non_coding_transcript_exon_variant	Exon 1 of 2	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs528996789; hg19: chr22-29196498;