22-28800759-G-C

Variant names:

• chr22-28800759-G-C
• rs2269576
• ENST00000585003.2:n.80G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The ENST00000585003.2(ENSG00000226471):​n.80G>C 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 0.00255 in 478,264 control chromosomes in the GnomAD database, including 43 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 0.00045 (2 hom., cov: 34)
  • Exomes 𝑓: 0.0035 (41 hom.)
• Consequence: ENSG00000226471 ENST00000585003.2 non_coding_transcript_exon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.07
• Publications: 2 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BS1: Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.00353 (1152/325908) while in subpopulation EAS AF = 0.0511 (1142/22366). AF 95% confidence interval is 0.0486. There are 41 homozygotes in GnomAdExome4. There are 538 alleles in the male GnomAdExome4 subpopulation. Median coverage is 4. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 gene

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.-235C>G		upstream_gene	N/A	NP_001073007.1	P17861-2
	XBP1	NM_005080.4		c.-235C>G		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.80G>C		non_coding_transcript_exon	Exon 1 of 1
	ENSG00000226471	ENST00000418292.1	TSL:3	n.34+22G>C		intron	N/A
	ENSG00000226471	ENST00000458080.2	TSL:3	n.55+22G>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000453 AC: 69 AN: 152238 Hom.: 2 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0131

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00353 AC: 1152 AN: 325908 Hom.: 41 Cov.: 4 AF XY: 0.00317 AC XY: 538 AN XY: 169964

African (AFR) AF: 0.00 AC: 0 AN: 7154

American (AMR) AF: 0.00 AC: 0 AN: 7364

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10456

East Asian (EAS) AF: 0.0511 AC: 1142 AN: 22366

South Asian (SAS) AF: 0.00 AC: 0 AN: 23570

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 26812

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1550

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 206528

Other (OTH) AF: 0.000497 AC: 10 AN: 20108

GnomAD4 genome AF: 0.000453 AC: 69 AN: 152356 Hom.: 2 Cov.: 34 AF XY: 0.000577 AC XY: 43 AN XY: 74510

African (AFR) AF: 0.00 AC: 0 AN: 41578

American (AMR) AF: 0.0000653 AC: 1 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.0131 AC: 68 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000907

Asia WGS AF: 0.00520 AC: 18 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.37
DANN	Benign	0.79
PhyloP100		-2.1
PromoterAI		0.15	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

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

Other links and lift over

dbSNP: rs2269576; hg19: chr22-29196747;