rs34842534

Variant names:

• chr22-28795910-G-A
• rs34842534
• ENST00000344347.6:c.573+137C>T

Your query was ambiguous. Multiple possible variants found:

• chr22-28795910-G-A
• chr22-28795910-G-T

Variant summary

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

The ENST00000344347.6(XBP1):​c.573+137C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00686 in 1,286,768 control chromosomes in the GnomAD database, including 53 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 0.0054 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0071 (50 hom.)
• Consequence: XBP1 ENST00000344347.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.139
• Publications: 1 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.00706 (8009/1134534) while in subpopulation MID AF = 0.0186 (70/3770). AF 95% confidence interval is 0.0151. There are 50 homozygotes in GnomAdExome4. There are 4105 alleles in the male GnomAdExome4 subpopulation. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XBP1	NM_001079539.2	c.573+137C>T		intron_variant	Intron 5 of 5		NP_001073007.1
XBP1	NM_001393999.1	c.423+137C>T		intron_variant	Intron 5 of 5		NP_001380928.1
XBP1	NM_005080.4	c.599+137C>T		intron_variant	Intron 4 of 4		NP_005071.2
XBP1	NM_001394000.1	c.449+137C>T		intron_variant	Intron 4 of 4		NP_001380929.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XBP1	ENST00000344347.6	c.573+137C>T		intron_variant	Intron 5 of 5	5		ENSP00000343155.5

Frequencies

GnomAD3 genomes AF: 0.00540 AC: 822 AN: 152116 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00143

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00865

Gnomad ASJ AF: 0.0199

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0102

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00715

Gnomad OTH AF: 0.00765

GnomAD4 exome AF: 0.00706 AC: 8009 AN: 1134534 Hom.: 50 AF XY: 0.00718 AC XY: 4105 AN XY: 571832

African (AFR) AF: 0.000893 AC: 24 AN: 26868

American (AMR) AF: 0.00638 AC: 239 AN: 37446

Ashkenazi Jewish (ASJ) AF: 0.0231 AC: 474 AN: 20548

East Asian (EAS) AF: 0.0000262 AC: 1 AN: 38122

South Asian (SAS) AF: 0.0105 AC: 735 AN: 70284

European-Finnish (FIN) AF: 0.000516 AC: 22 AN: 42606

Middle Eastern (MID) AF: 0.0186 AC: 70 AN: 3770

European-Non Finnish (NFE) AF: 0.00713 AC: 6032 AN: 845432

Other (OTH) AF: 0.00833 AC: 412 AN: 49458

GnomAD4 genome AF: 0.00541 AC: 824 AN: 152234 Hom.: 3 Cov.: 32 AF XY: 0.00559 AC XY: 416 AN XY: 74426

African (AFR) AF: 0.00142 AC: 59 AN: 41524

American (AMR) AF: 0.00863 AC: 132 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0199 AC: 69 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.0104 AC: 50 AN: 4818

European-Finnish (FIN) AF: 0.000565 AC: 6 AN: 10612

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.00716 AC: 487 AN: 68010

Other (OTH) AF: 0.00757 AC: 16 AN: 2114

Alfa AF: 0.00526 Hom.: 0

Bravo AF: 0.00598

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.94
DANN	Benign	0.60
PhyloP100		-0.14
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism

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: rs34842534; hg19: chr22-29191898;