Genetic Variant ERN1:c.283-5dupT (chr17-64075251-T-TA) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_001433.5(ERN1):c.283-5dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.162 in 1,212,756 control chromosomes in the GnomAD database, including 840 homozygotes. 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 0.041 ( 330 hom., cov: 0)

Exomes 𝑓: 0.18 ( 510 hom. )

Consequence

ERN1
NM_001433.5 splice_region, intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.278

Publications

1 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.142 is higher than 0.05.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes

AF:

0.0413

AC:

5611

AN:

135956

Hom.:

329

Cov.:

show subpopulations

Gnomad AFR

AF:

0.146

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0177

Gnomad ASJ

AF:

0.00953

Gnomad EAS

AF:

0.00225

Gnomad SAS

AF:

0.00743

Gnomad FIN

AF:

0.00882

Gnomad MID

AF:

0.0171

Gnomad NFE

AF:

0.00283

Gnomad OTH

AF:

0.0329

GnomAD2 exomes

AF:

0.214

AC:

10895

AN:

50844

AF XY:

0.218

show subpopulations

Gnomad AFR exome

AF:

0.210

Gnomad AMR exome

AF:

0.210

Gnomad ASJ exome

AF:

0.189

Gnomad EAS exome

AF:

0.204

Gnomad FIN exome

AF:

0.197

Gnomad NFE exome

AF:

0.217

Gnomad OTH exome

AF:

0.210

GnomAD4 exome

AF:

0.178

AC:

191156

AN:

1076784

Hom.:

510

Cov.:

AF XY:

0.179

AC XY:

95394

AN XY:

533620

show subpopulations

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

African (AFR)

AF:

0.184

AC:

3882

AN:

21100

American (AMR)

AF:

0.175

AC:

2443

AN:

13968

Ashkenazi Jewish (ASJ)

AF:

0.159

AC:

2958

AN:

18556

East Asian (EAS)

AF:

0.186

AC:

4824

AN:

25896

South Asian (SAS)

AF:

0.206

AC:

11822

AN:

57498

European-Finnish (FIN)

AF:

0.181

AC:

6503

AN:

35856

Middle Eastern (MID)

AF:

0.164

AC:

670

AN:

4086

European-Non Finnish (NFE)

AF:

0.176

AC:

150104

AN:

854644

Other (OTH)

AF:

0.176

AC:

7950

AN:

45180

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.302

Heterozygous variant carriers

13663

27327

40990

54654

68317

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5528

11056

16584

22112

27640

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0413

AC:

5618

AN:

135972

Hom.:

330

Cov.:

AF XY:

0.0402

AC XY:

2620

AN XY:

65168

show subpopulations

African (AFR)

AF:

0.145

AC:

4983

AN:

34266

American (AMR)

AF:

0.0178

AC:

247

AN:

13912

Ashkenazi Jewish (ASJ)

AF:

0.00953

AC:

AN:

3358

East Asian (EAS)

AF:

0.00205

AC:

AN:

4872

South Asian (SAS)

AF:

0.00747

AC:

AN:

4416

European-Finnish (FIN)

AF:

0.00882

AC:

AN:

6802

Middle Eastern (MID)

AF:

0.0187

AC:

AN:

268

European-Non Finnish (NFE)

AF:

0.00283

AC:

185

AN:

65296

Other (OTH)

AF:

0.0332

AC:

AN:

1898

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

217

434

651

868

1085

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

116

174

232

290

<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:

0.00

Hom.:

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)

(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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17-64075251-TAAAAAAAAAAA-TAAAAAAAAAAAA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over