17-64075251-TAAAAAAAAAAA-TAAAAAAAAA

Variant names:

• chr17-64075251-TAA-T
• rs5821420
• NM_001433.5:c.283-6_283-5delTT

Variant summary

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

The NM_001433.5(ERN1):​c.283-6_283-5delTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000289 in 1,286,654 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), 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 0.000022 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00032 (0 hom.)
• Consequence: ERN1 NM_001433.5 splice_region, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.651
• 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.

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.283-6_283-5delTT		splice_region intron	N/A	NP_001424.3	O75460-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ERN1	ENST00000433197.4	TSL:1 MANE Select	c.283-6_283-5delTT		splice_region intron	N/A	ENSP00000401445.2	O75460-1
	ERN1	ENST00000680433.1		c.283-6_283-5delTT		splice_region intron	N/A	ENSP00000506094.1	A0A7P0TAB0
	ERN1	ENST00000577567.5	TSL:5	n.148-6_148-5delTT		splice_region intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0000220 AC: 3 AN: 136062 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000719

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000146

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000153

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000321 AC: 369 AN: 1150574 Hom.: 0 AF XY: 0.000322 AC XY: 184 AN XY: 570860

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

African (AFR) AF: 0.000919 AC: 20 AN: 21766

American (AMR) AF: 0.000680 AC: 10 AN: 14716

Ashkenazi Jewish (ASJ) AF: 0.000305 AC: 6 AN: 19676

East Asian (EAS) AF: 0.000460 AC: 13 AN: 28260

South Asian (SAS) AF: 0.000443 AC: 27 AN: 60982

European-Finnish (FIN) AF: 0.000181 AC: 7 AN: 38602

Middle Eastern (MID) AF: 0.000230 AC: 1 AN: 4350

European-Non Finnish (NFE) AF: 0.000298 AC: 272 AN: 914050

Other (OTH) AF: 0.000270 AC: 13 AN: 48172

⚠️ 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: 0.0000220 AC: 3 AN: 136080 Hom.: 0 Cov.: 0 AF XY: 0.0000153 AC XY: 1 AN XY: 65228

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

African (AFR) AF: 0.00 AC: 0 AN: 34288

American (AMR) AF: 0.0000718 AC: 1 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: 0.000146 AC: 1 AN: 6826

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

European-Non Finnish (NFE) AF: 0.0000153 AC: 1 AN: 65344

Other (OTH) AF: 0.00 AC: 0 AN: 1902

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0000647710), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.65

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;