Genetic Variant NM_001433.5:c.283-6_283-5dupTT (chr17-64075251-T-TAA) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_ModerateBA1

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

Scores

Not classified

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.278

Variant links:

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]

ERN1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id 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 link	c.283-6_283-5dupTT		splice_region_variant, intron_variant	Intron 4 of 21	ENST00000433197.4	NP_001424.3	O75460-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERN1	ENST00000433197.4 link	c.283-5_283-4insTT		splice_region_variant, intron_variant	Intron 4 of 21	1	NM_001433.5	ENSP00000401445.2		O75460-1

Frequencies

GnomAD3 genomes

AF:

0.564

AC:

76512

AN:

135764

Hom.:

24389

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.361

AC:

18366

AN:

50844

Hom.:

1269

AF XY:

0.365

AC XY:

10613

AN XY:

29070

show subpopulations

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 SAS exome

AF:

0.382

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.:

AF XY:

0.426

AC XY:

238146

AN XY:

558634

show subpopulations

Gnomad4 AFR exome

AF:

0.134

Gnomad4 AMR exome

AF:

0.356

Gnomad4 ASJ exome

AF:

0.362

Gnomad4 EAS exome

AF:

0.416

Gnomad4 SAS exome

AF:

0.419

Gnomad4 FIN exome

AF:

0.413

Gnomad4 NFE exome

AF:

0.438

Gnomad4 OTH exome

AF:

0.411

GnomAD4 genome

AF:

0.563

AC:

76486

AN:

135782

Hom.:

24378

Cov.:

AF XY:

0.564

AC XY:

36684

AN XY:

65076

show subpopulations

Gnomad4 AFR

AF:

0.206

Gnomad4 AMR

AF:

0.593

Gnomad4 ASJ

AF:

0.598

Gnomad4 EAS

AF:

0.641

Gnomad4 SAS

AF:

0.749

Gnomad4 FIN

AF:

0.657

Gnomad4 NFE

AF:

0.713

Gnomad4 OTH

AF:

0.574

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

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

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over