chr17-64075251-T-TA

Variant names:

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

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
• 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: 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	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	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.: 0

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

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.: 29 AF XY: 0.179 AC XY: 95394 AN XY: 533620

⚠️ 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.

GnomAD4 genome AF: 0.0413 AC: 5618 AN: 135972 Hom.: 330 Cov.: 0 AF XY: 0.0402 AC XY: 2620 AN XY: 65168

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: 32 AN: 3358

East Asian (EAS) AF: 0.00205 AC: 10 AN: 4872

South Asian (SAS) AF: 0.00747 AC: 33 AN: 4416

European-Finnish (FIN) AF: 0.00882 AC: 60 AN: 6802

Middle Eastern (MID) AF: 0.0187 AC: 5 AN: 268

European-Non Finnish (NFE) AF: 0.00283 AC: 185 AN: 65296

Other (OTH) AF: 0.0332 AC: 63 AN: 1898

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		=100/0	polymorphism (auto)

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;