NM_001433.5:c.283-9_283-5dupTTTTT

Variant names:

• chr17-64075251-T-TAAAAA
• rs5821420
• NM_001433.5:c.283-9_283-5dupTTTTT

Variant summary

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

The NM_001433.5(ERN1):​c.283-9_283-5dupTTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000227 in 1,288,476 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00023 (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: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAd4 at 24 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERN1	NM_001433.5	MANE Select	c.283-9_283-5dupTTTTT		splice_region intron	N/A	NP_001424.3

Ensembl Transcripts

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

Frequencies

GnomAD3 genomes AF: 0.000176 AC: 24 AN: 136066 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0000877

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000144

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: 0.000275

Gnomad OTH AF: 0.000530

GnomAD4 exome AF: 0.000233 AC: 268 AN: 1152392 Hom.: 0 Cov.: 29 AF XY: 0.000252 AC XY: 144 AN XY: 571730

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

African (AFR) AF: 0.00 AC: 0 AN: 21956

American (AMR) AF: 0.000135 AC: 2 AN: 14782

Ashkenazi Jewish (ASJ) AF: 0.000101 AC: 2 AN: 19758

East Asian (EAS) AF: 0.00 AC: 0 AN: 28336

South Asian (SAS) AF: 0.000197 AC: 12 AN: 61042

European-Finnish (FIN) AF: 0.000155 AC: 6 AN: 38642

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4354

European-Non Finnish (NFE) AF: 0.000260 AC: 238 AN: 915250

Other (OTH) AF: 0.000166 AC: 8 AN: 48272

⚠️ 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: 0.000176 AC: 24 AN: 136084 Hom.: 0 Cov.: 0 AF XY: 0.000123 AC XY: 8 AN XY: 65230

African (AFR) AF: 0.0000875 AC: 3 AN: 34292

American (AMR) AF: 0.000144 AC: 2 AN: 13922

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3358

East Asian (EAS) AF: 0.00 AC: 0 AN: 4872

South Asian (SAS) AF: 0.00 AC: 0 AN: 4416

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6826

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

European-Non Finnish (NFE) AF: 0.000275 AC: 18 AN: 65344

Other (OTH) AF: 0.000526 AC: 1 AN: 1902

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.28

Splicing

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

Other links and lift over

dbSNP: rs5821420; hg19: chr17-62152611;