17-64103948-A-C

Variant names:

• chr17-64103948-A-C
• rs8076809
• NM_001433.5:c.55-5707T>G

Variant summary

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

The NM_001433.5(ERN1):​c.55-5707T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.427 in 151,964 control chromosomes in the GnomAD database, including 18,470 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 0.43 (18470 hom., cov: 31)
• Consequence: ERN1 NM_001433.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.720
• Publications: 7 publications found

Genes affected

ERN1 (HGNC:3449): (endoplasmic reticulum to nucleus signaling 1) This gene encodes the transmembrane protein kinase inositol-requiring enzyme 1. The encoded protein contains two functional catalytic domains, a serine/threonine-protein kinase domain and an endoribonuclease domain. This protein functions as a sensor of unfolded proteins in the endoplasmic reticulum (ER) and triggers an intracellular signaling pathway termed the unfolded protein response (UPR). The UPR is an ER stress response that is conserved from yeast to mammals and activates genes involved in degrading misfolded proteins, regulating protein synthesis and activating molecular chaperones. This protein specifically mediates the splicing and activation of the stress response transcription factor X-box binding protein 1. [provided by RefSeq, Aug 2017]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.808 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001433.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERN1	NM_001433.5	MANE Select	c.55-5707T>G		intron	N/A	NP_001424.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERN1	ENST00000433197.4	TSL:1 MANE Select	c.55-5707T>G		intron	N/A	ENSP00000401445.2
	ERN1	ENST00000680433.1		c.55-5707T>G		intron	N/A	ENSP00000506094.1
	ERN1	ENST00000680493.1		c.55-5707T>G		intron	N/A	ENSP00000505990.1

Frequencies

GnomAD3 genomes AF: 0.426 AC: 64740 AN: 151846 Hom.: 18421 Cov.: 31

Gnomad AFR AF: 0.815

Gnomad AMI AF: 0.342

Gnomad AMR AF: 0.389

Gnomad ASJ AF: 0.374

Gnomad EAS AF: 0.332

Gnomad SAS AF: 0.294

Gnomad FIN AF: 0.263

Gnomad MID AF: 0.316

Gnomad NFE AF: 0.246

Gnomad OTH AF: 0.401

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.427 AC: 64846 AN: 151964 Hom.: 18470 Cov.: 31 AF XY: 0.426 AC XY: 31607 AN XY: 74262

African (AFR) AF: 0.815 AC: 33794 AN: 41448

American (AMR) AF: 0.389 AC: 5935 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.374 AC: 1296 AN: 3468

East Asian (EAS) AF: 0.331 AC: 1708 AN: 5158

South Asian (SAS) AF: 0.293 AC: 1411 AN: 4810

European-Finnish (FIN) AF: 0.263 AC: 2771 AN: 10542

Middle Eastern (MID) AF: 0.316 AC: 93 AN: 294

European-Non Finnish (NFE) AF: 0.246 AC: 16688 AN: 67956

Other (OTH) AF: 0.398 AC: 838 AN: 2106

Alfa AF: 0.252 Hom.: 3215

Bravo AF: 0.456

Asia WGS AF: 0.295 AC: 1028 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.59
DANN	Benign	0.57
PhyloP100		-0.72
Mutation Taster		=100/0	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: rs8076809; hg19: chr17-62181308;