dbSNP rs1985961: ERN1:c.*4086G>A (chr17-64039902-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001433.5(ERN1):c.*4086G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.447 in 152,034 control chromosomes in the GnomAD database, including 18,462 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.45 ( 18457 hom., cov: 32)

Exomes 𝑓: 0.65 ( 5 hom. )

Consequence

ERN1
NM_001433.5 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.941

Publications

11 publications found

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 was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.93).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.606 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERN1	NM_001433.5 link	c.*4086G>A		3_prime_UTR_variant	Exon 22 of 22	ENST00000433197.4	NP_001424.3	O75460-1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
ERN1	ENST00000433197.4 link	c.*4086G>A	3_prime_UTR_variant	Exon 22 of 22	1	NM_001433.5	ENSP00000401445.2	O75460-1
ERN1	ENST00000680625.1 link	n.6938G>A	non_coding_transcript_exon_variant	Exon 21 of 21
ERN1	ENST00000680433.1 link	c.*5392G>A	3_prime_UTR_variant	Exon 20 of 20			ENSP00000506094.1	A0A7P0TAB0

Frequencies

GnomAD3 genomes

AF:

0.448

AC:

68022

AN:

151890

Hom.:

18457

Cov.:

show subpopulations

Gnomad AFR

AF:

0.133

Gnomad AMI

AF:

0.520

Gnomad AMR

AF:

0.451

Gnomad ASJ

AF:

0.505

Gnomad EAS

AF:

0.482

Gnomad SAS

AF:

0.601

Gnomad FIN

AF:

0.506

Gnomad MID

AF:

0.583

Gnomad NFE

AF:

0.611

Gnomad OTH

AF:

0.487

GnomAD4 exome

AF:

0.654

AC:

AN:

Hom.:

Cov.:

AF XY:

0.654

AC XY:

AN XY:

show subpopulations

African (AFR)

AF:

0.500

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AF:

0.500

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.667

AC:

AN:

Other (OTH)

AF:

0.750

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.518

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.447

AC:

68017

AN:

152008

Hom.:

18457

Cov.:

AF XY:

0.444

AC XY:

32986

AN XY:

74290

show subpopulations

African (AFR)

AF:

0.132

AC:

5486

AN:

41492

American (AMR)

AF:

0.450

AC:

6879

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.505

AC:

1754

AN:

3472

East Asian (EAS)

AF:

0.481

AC:

2485

AN:

5164

South Asian (SAS)

AF:

0.602

AC:

2903

AN:

4822

European-Finnish (FIN)

AF:

0.506

AC:

5316

AN:

10514

Middle Eastern (MID)

AF:

0.579

AC:

169

AN:

292

European-Non Finnish (NFE)

AF:

0.611

AC:

41515

AN:

67958

Other (OTH)

AF:

0.491

AC:

1037

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1623

3246

4870

6493

8116

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

622

1244

1866

2488

3110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.542

Hom.:

54092

Bravo

AF:

0.424

Asia WGS

AF:

0.542

AC:

1882

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

0.17

(source)

DANN

Benign

0.72

PhyloP100

-0.94

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over