17-64075251-TAAAAAAAAAAA-TAAAAAAAAAAAAAA

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

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
• Publications: 1 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 -8 ACMG points.

• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0302 (4105/136038) while in subpopulation NFE AF = 0.0448 (2924/65310). AF 95% confidence interval is 0.0434. There are 91 homozygotes in GnomAd4. There are 1903 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 4105 AD gene.

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

GnomAD2 exomes AF: 0.0589 AC: 2994 AN: 50844 AF XY: 0.0609

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 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

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

African (AFR) AF: 0.00905 AC: 198 AN: 21888

American (AMR) AF: 0.0440 AC: 641 AN: 14582

Ashkenazi Jewish (ASJ) AF: 0.0331 AC: 642 AN: 19406

East Asian (EAS) AF: 0.0234 AC: 655 AN: 27962

South Asian (SAS) AF: 0.0532 AC: 3163 AN: 59480

European-Finnish (FIN) AF: 0.0605 AC: 2296 AN: 37968

Middle Eastern (MID) AF: 0.0326 AC: 140 AN: 4292

European-Non Finnish (NFE) AF: 0.0763 AC: 68846 AN: 902474

Other (OTH) AF: 0.0595 AC: 2827 AN: 47546

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

African (AFR) AF: 0.00954 AC: 327 AN: 34288

American (AMR) AF: 0.0256 AC: 356 AN: 13916

Ashkenazi Jewish (ASJ) AF: 0.00744 AC: 25 AN: 3358

East Asian (EAS) AF: 0.00164 AC: 8 AN: 4870

South Asian (SAS) AF: 0.0140 AC: 62 AN: 4416

European-Finnish (FIN) AF: 0.0404 AC: 276 AN: 6826

Middle Eastern (MID) AF: 0.0299 AC: 8 AN: 268

European-Non Finnish (NFE) AF: 0.0448 AC: 2924 AN: 65310

Other (OTH) AF: 0.0352 AC: 67 AN: 1902

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.28
Mutation Taster		=100/0	polymorphism (auto)

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;