ENST00000344347.6:c.453+395A>T

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000344347.6(XBP1):​c.453+395A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: XBP1 ENST00000344347.6 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XBP1	NM_001079539.2	c.453+395A>T		intron_variant	Intron 3 of 5		NP_001073007.1
XBP1	NM_001393999.1	c.303+395A>T		intron_variant	Intron 3 of 5		NP_001380928.1
XBP1	NM_005080.4	c.453+395A>T		intron_variant	Intron 3 of 4		NP_005071.2
XBP1	NM_001394000.1	c.303+395A>T		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>T		intron_variant	Intron 3 of 5	5		ENSP00000343155.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 21698 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 11182

African (AFR) AF: 0.00 AC: 0 AN: 406

American (AMR) AF: 0.00 AC: 0 AN: 1420

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 570

East Asian (EAS) AF: 0.00 AC: 0 AN: 562

South Asian (SAS) AF: 0.00 AC: 0 AN: 1686

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 938

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 80

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 14674

Other (OTH) AF: 0.00 AC: 0 AN: 1362

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	3.9
DANN	Benign	0.84
PhyloP100		-0.044

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;