17-64075251-TAAAAAAAAAAA-TAAAAAAAAAAAAA

Variant names:

• chr17-64075251-T-TAA
• rs5821420
• NM_001433.5:c.283-6_283-5dupTT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_001433.5(ERN1):​c.283-6_283-5dupTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.56 (24378 hom., cov: 0)
  • Exomes 𝑓: 0.43 (18004 hom.)
  • Failed GnomAD Quality Control
• Consequence: ERN1 NM_001433.5 splice_region, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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 -10 ACMG points.

• BP6: Variant 17-64075251-T-TAA is Benign according to our data. Variant chr17-64075251-T-TAA is described in ClinVar as Benign. ClinVar VariationId is 402835.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.728 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERN1	NM_001433.5	c.283-6_283-5dupTT		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_283-4insTT		splice_region_variant, intron_variant	Intron 4 of 21	1	NM_001433.5	ENSP00000401445.2

Frequencies

GnomAD3 genomes AF: 0.564 AC: 76512 AN: 135764 Hom.: 24389 Cov.: 0

Gnomad AFR AF: 0.206

Gnomad AMI AF: 0.651

Gnomad AMR AF: 0.592

Gnomad ASJ AF: 0.598

Gnomad EAS AF: 0.641

Gnomad SAS AF: 0.748

Gnomad FIN AF: 0.657

Gnomad MID AF: 0.647

Gnomad NFE AF: 0.713

Gnomad OTH AF: 0.573

GnomAD2 exomes AF: 0.361 AC: 18366 AN: 50844 AF XY: 0.365

Gnomad AFR exome AF: 0.0950

Gnomad AMR exome AF: 0.306

Gnomad ASJ exome AF: 0.309

Gnomad EAS exome AF: 0.301

Gnomad FIN exome AF: 0.407

Gnomad NFE exome AF: 0.381

Gnomad OTH exome AF: 0.342

GnomAD4 exome Data not reliable, filtered out with message: InbreedingCoeff AF: 0.426 AC: 480528 AN: 1128276 Hom.: 18004 Cov.: 29 AF XY: 0.426 AC XY: 238146 AN XY: 558634

African (AFR) AF: 0.134 AC: 2889 AN: 21524

American (AMR) AF: 0.356 AC: 5104 AN: 14346

Ashkenazi Jewish (ASJ) AF: 0.362 AC: 6885 AN: 19036

East Asian (EAS) AF: 0.416 AC: 11420 AN: 27468

South Asian (SAS) AF: 0.419 AC: 24660 AN: 58906

European-Finnish (FIN) AF: 0.413 AC: 15517 AN: 37554

Middle Eastern (MID) AF: 0.391 AC: 1656 AN: 4240

European-Non Finnish (NFE) AF: 0.438 AC: 393045 AN: 898172

Other (OTH) AF: 0.411 AC: 19352 AN: 47030

GnomAD4 genome AF: 0.563 AC: 76486 AN: 135782 Hom.: 24378 Cov.: 0 AF XY: 0.564 AC XY: 36684 AN XY: 65076

African (AFR) AF: 0.206 AC: 7040 AN: 34224

American (AMR) AF: 0.593 AC: 8204 AN: 13846

Ashkenazi Jewish (ASJ) AF: 0.598 AC: 2006 AN: 3356

East Asian (EAS) AF: 0.641 AC: 3116 AN: 4862

South Asian (SAS) AF: 0.749 AC: 3299 AN: 4404

European-Finnish (FIN) AF: 0.657 AC: 4461 AN: 6788

Middle Eastern (MID) AF: 0.642 AC: 172 AN: 268

European-Non Finnish (NFE) AF: 0.713 AC: 46526 AN: 65258

Other (OTH) AF: 0.574 AC: 1089 AN: 1896

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency

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; COSMIC: COSV105939784; COSMIC: COSV105939784;