17-64075251-TAAAAAAAAAAA-TAAAAAAAAAA

Variant names:

• chr17-64075251-TA-T
• rs5821420
• NM_001433.5:c.283-5delT

Variant summary

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

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. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. 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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.278
• Publications: 1 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

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

Frequencies

GnomAD3 genomes AF: 0.000515 AC: 70 AN: 136040 Hom.: 0 Cov.: 0

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

GnomAD2 exomes AF: 0.0401 AC: 2041 AN: 50844 AF XY: 0.0374

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 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.: 0 Cov.: 29 AF XY: 0.0182 AC XY: 10260 AN XY: 564524

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

African (AFR) AF: 0.0753 AC: 1553 AN: 20612

American (AMR) AF: 0.0432 AC: 624 AN: 14446

Ashkenazi Jewish (ASJ) AF: 0.0393 AC: 754 AN: 19182

East Asian (EAS) AF: 0.0268 AC: 741 AN: 27652

South Asian (SAS) AF: 0.0181 AC: 1090 AN: 60210

European-Finnish (FIN) AF: 0.0175 AC: 665 AN: 38052

Middle Eastern (MID) AF: 0.0224 AC: 95 AN: 4250

European-Non Finnish (NFE) AF: 0.0162 AC: 14691 AN: 906222

Other (OTH) AF: 0.0215 AC: 1021 AN: 47532

⚠️ 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.

GnomAD4 genome AF: 0.000522 AC: 71 AN: 136058 Hom.: 0 Cov.: 0 AF XY: 0.000659 AC XY: 43 AN XY: 65212

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

African (AFR) AF: 0.000554 AC: 19 AN: 34288

American (AMR) AF: 0.000934 AC: 13 AN: 13914

Ashkenazi Jewish (ASJ) AF: 0.000298 AC: 1 AN: 3358

East Asian (EAS) AF: 0.000411 AC: 2 AN: 4872

South Asian (SAS) AF: 0.000226 AC: 1 AN: 4416

European-Finnish (FIN) AF: 0.00249 AC: 17 AN: 6820

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 268

European-Non Finnish (NFE) AF: 0.000260 AC: 17 AN: 65338

Other (OTH) AF: 0.000526 AC: 1 AN: 1900

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.28
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs5821420; hg19: chr17-62152611;