17-64075251-TAAAAAAAAAAA-TAAAAAAAAAAAAAAA

Variant names:

• chr17-64075251-T-TAAAA
• rs5821420
• NM_001433.5:c.283-8_283-5dupTTTT

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_001433.5(ERN1):​c.283-8_283-5dupTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0018 in 1,285,602 control chromosomes in the GnomAD database, including 2 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000044 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0020 (2 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 Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAd4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERN1	NM_001433.5	c.283-8_283-5dupTTTT		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_283-4insTTTT		splice_region_variant, intron_variant	Intron 4 of 21	1	NM_001433.5	ENSP00000401445.2

Frequencies

GnomAD3 genomes AF: 0.0000441 AC: 6 AN: 136060 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000293

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000612

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00417 AC: 212 AN: 50844 Hom.: 0 AF XY: 0.00451 AC XY: 131 AN XY: 29070

Gnomad AFR exome AF: 0.00236

Gnomad AMR exome AF: 0.00367

Gnomad ASJ exome AF: 0.00382

Gnomad EAS exome AF: 0.00160

Gnomad SAS exome AF: 0.00473

Gnomad FIN exome AF: 0.00342

Gnomad NFE exome AF: 0.00478

Gnomad OTH exome AF: 0.00275

GnomAD4 exome AF: 0.00201 AC: 2305 AN: 1149542 Hom.: 2 Cov.: 29 AF XY: 0.00195 AC XY: 1115 AN XY: 570336

Gnomad4 AFR exome AF: 0.000273

Gnomad4 AMR exome AF: 0.00142

Gnomad4 ASJ exome AF: 0.00101

Gnomad4 EAS exome AF: 0.000459

Gnomad4 SAS exome AF: 0.00156

Gnomad4 FIN exome AF: 0.00174

Gnomad4 NFE exome AF: 0.00220

Gnomad4 OTH exome AF: 0.00143

GnomAD4 genome AF: 0.0000441 AC: 6 AN: 136060 Hom.: 0 Cov.: 0 AF XY: 0.0000920 AC XY: 6 AN XY: 65194

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000293

Gnomad4 NFE AF: 0.0000612

Gnomad4 OTH AF: 0.00

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;