Genetic Variant NM_001433.5:c.283-5delT (chr17-64075251-TA-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BA1

The NM_001433.5(ERN1):c.283-5delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0167 in 1,274,216 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00052 ( 0 hom., cov: 0)

Exomes 𝑓: 0.019 ( 0 hom. )

Consequence

ERN1
NM_001433.5 splice_region, intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BA1

GnomAdExome4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0722 is higher than 0.05.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes

AF:

0.000515

AC:

AN:

136040

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000526

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000935

Gnomad ASJ

AF:

0.000298

Gnomad EAS

AF:

0.000409

Gnomad SAS

AF:

0.000225

Gnomad FIN

AF:

0.00249

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000260

Gnomad OTH

AF:

0.000530

GnomAD3 exomes

AF:

0.0401

AC:

2041

AN:

50844

Hom.:

AF XY:

0.0374

AC XY:

1088

AN XY:

29070

show subpopulations

Gnomad AFR exome

AF:

0.125

Gnomad AMR exome

AF:

0.0755

Gnomad ASJ exome

AF:

0.0611

Gnomad EAS exome

AF:

0.0923

Gnomad SAS exome

AF:

0.0276

Gnomad FIN exome

AF:

0.0211

Gnomad NFE exome

AF:

0.0314

Gnomad OTH exome

AF:

0.0467

GnomAD4 exome

AF:

0.0187

AC:

21234

AN:

1138158

Hom.:

Cov.:

AF XY:

0.0182

AC XY:

10260

AN XY:

564524

show subpopulations

Gnomad4 AFR exome

AF:

0.0753

Gnomad4 AMR exome

AF:

0.0432

Gnomad4 ASJ exome

AF:

0.0393

Gnomad4 EAS exome

AF:

0.0268

Gnomad4 SAS exome

AF:

0.0181

Gnomad4 FIN exome

AF:

0.0175

Gnomad4 NFE exome

AF:

0.0162

Gnomad4 OTH exome

AF:

0.0215

GnomAD4 genome

AF:

0.000522

AC:

AN:

136058

Hom.:

Cov.:

AF XY:

0.000659

AC XY:

AN XY:

65212

show subpopulations

Gnomad4 AFR

AF:

0.000554

Gnomad4 AMR

AF:

0.000934

Gnomad4 ASJ

AF:

0.000298

Gnomad4 EAS

AF:

0.000411

Gnomad4 SAS

AF:

0.000226

Gnomad4 FIN

AF:

0.00249

Gnomad4 NFE

AF:

0.000260

Gnomad4 OTH

AF:

0.000526

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over