17-64075251-TAAAAAAAAAAA-TAAAAAAAAAAAAAAAAAAA

Variant names:

• chr17-64075251-T-TAAAAAAAA
• rs5821420
• NM_001433.5:c.283-12_283-5dupTTTTTTTT

Variant summary

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

The NM_001433.5(ERN1):​c.283-12_283-5dupTTTTTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000867 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: 8.7e-7 (0 hom.)
• Consequence: ERN1 NM_001433.5 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.278
• 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERN1	NM_001433.5	c.283-12_283-5dupTTTTTTTT		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_283-4insTTTTTTTT		splice_region_variant, intron_variant	Intron 4 of 21	1	NM_001433.5	ENSP00000401445.2

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome AF: 8.67e-7 AC: 1 AN: 1152810 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 571964

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

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: 0.00000109 AC: 1 AN: 915586

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

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.28

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;