NM_001433.5:c.283-7_283-5dupTTT

Variant names:

• chr17-64075251-T-TAAA
• rs5821420
• NM_001433.5:c.283-7_283-5dupTTT

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

The NM_001433.5(ERN1):​c.283-7_283-5dupTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0657 in 1,271,636 control chromosomes in the GnomAD database, including 422 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.030 (91 hom., cov: 0)
  • Exomes 𝑓: 0.070 (331 hom.)
• Consequence: ERN1 NM_001433.5 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.278

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

Verdict is Benign. Variant got -8 ACMG points.

• BA1: GnomAdExome4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0758 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERN1	NM_001433.5	c.283-7_283-5dupTTT		splice_region_variant, intron_variant	Intron 4 of 21	ENST00000433197.4	NP_001424.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERN1	ENST00000433197.4	c.283-5_283-4insTTT		splice_region_variant, intron_variant	Intron 4 of 21	1	NM_001433.5	ENSP00000401445.2

Frequencies

GnomAD3 genomes AF: 0.0302 AC: 4107 AN: 136020 Hom.: 91 Cov.: 0

Gnomad AFR AF: 0.00956

Gnomad AMI AF: 0.0588

Gnomad AMR AF: 0.0256

Gnomad ASJ AF: 0.00744

Gnomad EAS AF: 0.00164

Gnomad SAS AF: 0.0146

Gnomad FIN AF: 0.0404

Gnomad MID AF: 0.0274

Gnomad NFE AF: 0.0448

Gnomad OTH AF: 0.0350

GnomAD3 exomes AF: 0.0589 AC: 2994 AN: 50844 Hom.: 59 AF XY: 0.0609 AC XY: 1771 AN XY: 29070

Gnomad AFR exome AF: 0.0136

Gnomad AMR exome AF: 0.0472

Gnomad ASJ exome AF: 0.0436

Gnomad EAS exome AF: 0.0347

Gnomad SAS exome AF: 0.0646

Gnomad FIN exome AF: 0.0651

Gnomad NFE exome AF: 0.0647

Gnomad OTH exome AF: 0.0495

GnomAD4 exome AF: 0.0699 AC: 79408 AN: 1135598 Hom.: 331 Cov.: 29 AF XY: 0.0690 AC XY: 38819 AN XY: 562926

Gnomad4 AFR exome AF: 0.00905

Gnomad4 AMR exome AF: 0.0440

Gnomad4 ASJ exome AF: 0.0331

Gnomad4 EAS exome AF: 0.0234

Gnomad4 SAS exome AF: 0.0532

Gnomad4 FIN exome AF: 0.0605

Gnomad4 NFE exome AF: 0.0763

Gnomad4 OTH exome AF: 0.0595

GnomAD4 genome AF: 0.0302 AC: 4105 AN: 136038 Hom.: 91 Cov.: 0 AF XY: 0.0292 AC XY: 1903 AN XY: 65206

Gnomad4 AFR AF: 0.00954

Gnomad4 AMR AF: 0.0256

Gnomad4 ASJ AF: 0.00744

Gnomad4 EAS AF: 0.00164

Gnomad4 SAS AF: 0.0140

Gnomad4 FIN AF: 0.0404

Gnomad4 NFE AF: 0.0448

Gnomad4 OTH AF: 0.0352

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs5821420; hg19: chr17-62152611;