22-28800769-G-C

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000585003.2(ENSG00000226471):​n.90G>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 0.375 in 474,570 control chromosomes in the GnomAD database, including 36,766 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as risk factor (no stars).

• Frequency:
  • Genomes: 𝑓 0.40 (13291 hom., cov: 34)
  • Exomes 𝑓: 0.36 (23475 hom.)
• Consequence: ENSG00000226471 ENST00000585003.2 non_coding_transcript_exon
• Clinical Significance: risk factor no assertion criteria provided O:1
• 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.658 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XBP1	NM_001079539.2	c.-245C>G		upstream_gene_variant		ENST00000344347.6	NP_001073007.1
XBP1	NM_005080.4	c.-245C>G		upstream_gene_variant			NP_005071.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XBP1	ENST00000344347.6	c.-245C>G		upstream_gene_variant		5	NM_001079539.2	ENSP00000343155.5

Frequencies

GnomAD3 genomes AF: 0.397 AC: 60407 AN: 152116 Hom.: 13263 Cov.: 34

Gnomad AFR AF: 0.549

Gnomad AMI AF: 0.185

Gnomad AMR AF: 0.296

Gnomad ASJ AF: 0.331

Gnomad EAS AF: 0.677

Gnomad SAS AF: 0.537

Gnomad FIN AF: 0.373

Gnomad MID AF: 0.339

Gnomad NFE AF: 0.307

Gnomad OTH AF: 0.369

GnomAD4 exome AF: 0.364 AC: 117453 AN: 322336 Hom.: 23475 Cov.: 3 AF XY: 0.368 AC XY: 61889 AN XY: 168248

African (AFR) AF: 0.541 AC: 3807 AN: 7042

American (AMR) AF: 0.314 AC: 2291 AN: 7306

Ashkenazi Jewish (ASJ) AF: 0.306 AC: 3185 AN: 10408

East Asian (EAS) AF: 0.680 AC: 15195 AN: 22332

South Asian (SAS) AF: 0.505 AC: 11919 AN: 23586

European-Finnish (FIN) AF: 0.377 AC: 10094 AN: 26792

Middle Eastern (MID) AF: 0.393 AC: 609 AN: 1550

European-Non Finnish (NFE) AF: 0.310 AC: 62958 AN: 203320

Other (OTH) AF: 0.370 AC: 7395 AN: 20000

GnomAD4 genome AF: 0.397 AC: 60491 AN: 152234 Hom.: 13291 Cov.: 34 AF XY: 0.401 AC XY: 29852 AN XY: 74434

African (AFR) AF: 0.549 AC: 22807 AN: 41534

American (AMR) AF: 0.296 AC: 4531 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.331 AC: 1149 AN: 3468

East Asian (EAS) AF: 0.677 AC: 3503 AN: 5176

South Asian (SAS) AF: 0.536 AC: 2593 AN: 4834

European-Finnish (FIN) AF: 0.373 AC: 3950 AN: 10594

Middle Eastern (MID) AF: 0.340 AC: 100 AN: 294

European-Non Finnish (NFE) AF: 0.307 AC: 20899 AN: 68012

Other (OTH) AF: 0.374 AC: 790 AN: 2114

Alfa AF: 0.233 Hom.: 555

Bravo AF: 0.395

Asia WGS AF: 0.611 AC: 2127 AN: 3478

ClinVar

Significance: risk factor

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

MAJOR AFFECTIVE DISORDER 7, SUSCEPTIBILITY TO Other:1

Sep 02, 2004

OMIM

Significance: risk factor

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.053
DANN	Benign	0.59
PhyloP100		-1.2
PromoterAI		-0.16	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: rs2269577; hg19: chr22-29196757;