Genetic Variant ERN1:c.283-8_283-5delTTTT (chr17-64075251-TAAAA-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001433.5(ERN1):c.283-8_283-5delTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000026 in 1,152,798 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 0.0 ( 0 hom., cov: 0)

Exomes 𝑓: 0.0000026 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ERN1
NM_001433.5 splice_region, intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.61

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: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERN1	NM_001433.5 link	c.283-8_283-5delTTTT		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.283-8_283-5delTTTT		splice_region_variant, intron_variant	Intron 4 of 21	1	NM_001433.5	ENSP00000401445.2

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

136062

Hom.:

Cov.:

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000260

AC:

AN:

1152798

Hom.:

AF XY:

0.00000175

AC XY:

AN XY:

571960

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

21962

American (AMR)

AF:

0.00

AC:

AN:

14784

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19768

East Asian (EAS)

AF:

0.00

AC:

AN:

28338

South Asian (SAS)

AF:

0.00

AC:

AN:

61076

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38654

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4352

European-Non Finnish (NFE)

AF:

0.00000109

AC:

AN:

915576

Other (OTH)

AF:

0.0000414

AC:

AN:

48288

⚠️ 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: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

136062

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

65194

African (AFR)

AF:

0.00

AC:

AN:

34222

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:

0.00

AC:

AN:

6826

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

65352

Other (OTH)

AF:

0.00

AC:

AN:

1888

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.6

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-TAAAAAAA

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