22-28800769-G-T

Variant names:

• chr22-28800769-G-T
• rs2269577
• ENST00000585003.2:n.90G>T

Variant summary

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

The ENST00000585003.2(ENSG00000226471):​n.90G>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 322,700 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: 34)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: ENSG00000226471 ENST00000585003.2 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.24
• Publications: 27 publications found

Genes affected

ENSG00000226471 (HGNC:):

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=-0.79).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000585003.2. 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.-245C>A		upstream_gene	N/A	NP_001073007.1
	XBP1	NM_005080.4		c.-245C>A		upstream_gene	N/A	NP_005071.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENSG00000226471	ENST00000585003.2	TSL:6	n.90G>T		non_coding_transcript_exon	Exon 1 of 1
	ENSG00000226471	ENST00000418292.1	TSL:3	n.34+32G>T		intron	N/A
	ENSG00000226471	ENST00000458080.2	TSL:3	n.55+32G>T		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 0.00000620 AC: 2 AN: 322700 Hom.: 0 Cov.: 3 AF XY: 0.00 AC XY: 0 AN XY: 168434

African (AFR) AF: 0.00 AC: 0 AN: 7062

American (AMR) AF: 0.00 AC: 0 AN: 7314

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10418

East Asian (EAS) AF: 0.00 AC: 0 AN: 22348

South Asian (SAS) AF: 0.00 AC: 0 AN: 23608

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 26830

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1554

European-Non Finnish (NFE) AF: 0.00000983 AC: 2 AN: 203544

Other (OTH) AF: 0.00 AC: 0 AN: 20022

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.050
DANN	Benign	0.31
PhyloP100		-1.2
PromoterAI		-0.076	Neutral

Splicing

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

Other links and lift over

dbSNP: rs2269577; hg19: chr22-29196757;