chr22-28800506-C-T

Variant names:

• chr22-28800506-C-T
• rs5762809
• ENST00000344347.6:c.19G>A

Variant summary

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

The ENST00000344347.6(XBP1):​c.19G>A​(p.Ala7Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.133 in 1,488,060 control chromosomes in the GnomAD database, including 14,817 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.10 (1096 hom., cov: 33)
  • Exomes 𝑓: 0.14 (13721 hom.)
• Consequence: XBP1 ENST00000344347.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.826
• Publications: 22 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]

ENSG00000226471 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001998186).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.268 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XBP1	NM_001079539.2	c.19G>A	p.Ala7Thr	missense_variant	Exon 1 of 6		NP_001073007.1
XBP1	NM_005080.4	c.19G>A	p.Ala7Thr	missense_variant	Exon 1 of 5		NP_005071.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XBP1	ENST00000344347.6	c.19G>A	p.Ala7Thr	missense_variant	Exon 1 of 6	5		ENSP00000343155.5

Frequencies

GnomAD3 genomes AF: 0.103 AC: 15623 AN: 152086 Hom.: 1098 Cov.: 33

Gnomad AFR AF: 0.0244

Gnomad AMI AF: 0.0872

Gnomad AMR AF: 0.0814

Gnomad ASJ AF: 0.130

Gnomad EAS AF: 0.206

Gnomad SAS AF: 0.281

Gnomad FIN AF: 0.100

Gnomad MID AF: 0.204

Gnomad NFE AF: 0.133

Gnomad OTH AF: 0.131

GnomAD2 exomes AF: 0.146 AC: 12511 AN: 85718 AF XY: 0.157

Gnomad AFR exome AF: 0.0252

Gnomad AMR exome AF: 0.0596

Gnomad ASJ exome AF: 0.132

Gnomad EAS exome AF: 0.206

Gnomad FIN exome AF: 0.101

Gnomad NFE exome AF: 0.133

Gnomad OTH exome AF: 0.155

GnomAD4 exome AF: 0.136 AC: 182292 AN: 1335866 Hom.: 13721 Cov.: 32 AF XY: 0.140 AC XY: 92656 AN XY: 659754

African (AFR) AF: 0.0231 AC: 614 AN: 26614

American (AMR) AF: 0.0672 AC: 1793 AN: 26688

Ashkenazi Jewish (ASJ) AF: 0.130 AC: 2969 AN: 22894

East Asian (EAS) AF: 0.206 AC: 6204 AN: 30074

South Asian (SAS) AF: 0.265 AC: 19478 AN: 73512

European-Finnish (FIN) AF: 0.108 AC: 3743 AN: 34746

Middle Eastern (MID) AF: 0.216 AC: 1143 AN: 5292

European-Non Finnish (NFE) AF: 0.131 AC: 138605 AN: 1060608

Other (OTH) AF: 0.140 AC: 7743 AN: 55438

GnomAD4 genome AF: 0.103 AC: 15614 AN: 152194 Hom.: 1096 Cov.: 33 AF XY: 0.104 AC XY: 7725 AN XY: 74428

African (AFR) AF: 0.0243 AC: 1011 AN: 41534

American (AMR) AF: 0.0813 AC: 1244 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.130 AC: 452 AN: 3472

East Asian (EAS) AF: 0.206 AC: 1062 AN: 5166

South Asian (SAS) AF: 0.280 AC: 1353 AN: 4824

European-Finnish (FIN) AF: 0.100 AC: 1063 AN: 10612

Middle Eastern (MID) AF: 0.212 AC: 62 AN: 292

European-Non Finnish (NFE) AF: 0.133 AC: 9013 AN: 67986

Other (OTH) AF: 0.130 AC: 275 AN: 2108

Alfa AF: 0.125 Hom.: 759

Bravo AF: 0.0958

TwinsUK AF: 0.146 AC: 543

ALSPAC AF: 0.130 AC: 501

ExAC AF: 0.0871 AC: 8079

Asia WGS AF: 0.238 AC: 827 AN: 3466

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.10	T;T;.;.
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.24
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.71	T;T;T;.
MetaRNN	Benign	0.0020	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.0	M;.;M;M
PhyloP100		0.83
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.49	N;N;.;N
REVEL	Benign	0.054
Sift	Benign	0.033	D;D;.;D
Sift4G	Benign	0.32	T;T;T;T
Polyphen		0.017	.;.;B;B
Vest4		0.30
MPC		0.85
ClinPred		0.047	T
GERP RS		3.4
PromoterAI		0.027	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.078
gMVP		0.41
Mutation Taster		=95/5	polymorphism (auto)

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: rs5762809; hg19: chr22-29196494; COSMIC: COSV53274088; COSMIC: COSV53274088;