Genetic Variant ERN1:c.283-8_283-5dupTTTT (chr17-64075251-T-TAAAA) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_001433.5(ERN1):c.283-8_283-5dupTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0018 in 1,285,602 control chromosomes in the GnomAD database, including 2 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000044 ( 0 hom., cov: 0)

Exomes 𝑓: 0.0020 ( 2 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: Likely_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAd4 at 6 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001433.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERN1	NM_001433.5	MANE Select	c.283-8_283-5dupTTTT		splice_region intron	N/A	NP_001424.3	O75460-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ERN1	ENST00000433197.4	TSL:1 MANE Select	c.283-5_283-4insTTTT	splice_region intron	N/A	ENSP00000401445.2	O75460-1
ERN1	ENST00000680433.1		c.283-5_283-4insTTTT	splice_region intron	N/A	ENSP00000506094.1	A0A7P0TAB0
ERN1	ENST00000577567.5	TSL:5	n.148-5_148-4insTTTT	splice_region intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.0000441

AC:

AN:

136060

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000293

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000612

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00417

AC:

212

AN:

50844

AF XY:

0.00451

show subpopulations

Gnomad AFR exome

AF:

0.00236

Gnomad AMR exome

AF:

0.00367

Gnomad ASJ exome

AF:

0.00382

Gnomad EAS exome

AF:

0.00160

Gnomad FIN exome

AF:

0.00342

Gnomad NFE exome

AF:

0.00478

Gnomad OTH exome

AF:

0.00275

GnomAD4 exome

AF:

0.00201

AC:

2305

AN:

1149542

Hom.:

Cov.:

AF XY:

0.00195

AC XY:

1115

AN XY:

570336

show subpopulations

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

African (AFR)

AF:

0.000273

AC:

AN:

21954

American (AMR)

AF:

0.00142

AC:

AN:

14752

Ashkenazi Jewish (ASJ)

AF:

0.00101

AC:

AN:

19730

East Asian (EAS)

AF:

0.000459

AC:

AN:

28298

South Asian (SAS)

AF:

0.00156

AC:

AN:

60812

European-Finnish (FIN)

AF:

0.00174

AC:

AN:

38572

Middle Eastern (MID)

AF:

0.000921

AC:

AN:

4344

European-Non Finnish (NFE)

AF:

0.00220

AC:

2010

AN:

912926

Other (OTH)

AF:

0.00143

AC:

AN:

48154

⚠️ 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: 0.289

Heterozygous variant carriers

187

374

562

749

936

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

172

258

344

430

<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:

0.0000441

AC:

AN:

136060

Hom.:

Cov.:

AF XY:

0.0000920

AC XY:

AN XY:

65194

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

34218

American (AMR)

AF:

0.00

AC:

AN:

13912

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3358

East Asian (EAS)

AF:

0.00

AC:

AN:

4888

South Asian (SAS)

AF:

0.00

AC:

AN:

4440

European-Finnish (FIN)

AF:

0.000293

AC:

AN:

6826

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000612

AC:

AN:

65354

Other (OTH)

AF:

0.00

AC:

AN:

1888

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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 v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.28

Mutation Taster

=100/0

polymorphism

(source)

Splicing

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

Publications

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17-64075251-TAAAAAAAAAAA-TAAAAAAAAAAAAAAA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over