17-64075251-TAAAAAAAAAAA-TAAAAA

Variant names:

• chr17-64075251-TAAAAAA-T
• rs5821420
• NM_001433.5:c.283-10_283-5delTTTTTT

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001433.5(ERN1):​c.283-10_283-5delTTTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000347 in 1,152,810 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 0)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: ERN1 NM_001433.5 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.61
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.283-10_283-5delTTTTTT		splice_region 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.283-10_283-5delTTTTTT		splice_region intron	N/A	ENSP00000401445.2
	ERN1	ENST00000680433.1		c.283-10_283-5delTTTTTT		splice_region intron	N/A	ENSP00000506094.1
	ERN1	ENST00000577567.5	TSL:5	n.148-10_148-5delTTTTTT		splice_region intron	N/A

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome AF: 0.00000347 AC: 4 AN: 1152810 Hom.: 0 AF XY: 0.00000525 AC XY: 3 AN XY: 571964

African (AFR) AF: 0.00 AC: 0 AN: 21962

American (AMR) AF: 0.00 AC: 0 AN: 14784

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19768

East Asian (EAS) AF: 0.00 AC: 0 AN: 28338

South Asian (SAS) AF: 0.00 AC: 0 AN: 61076

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38654

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4354

European-Non Finnish (NFE) AF: 0.00000437 AC: 4 AN: 915586

Other (OTH) AF: 0.00 AC: 0 AN: 48288

GnomAD4 genome Cov.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.6

Splicing

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

Other links and lift over

dbSNP: rs5821420; hg19: chr17-62152611;