17-64049169-C-T

Variant names:

• chr17-64049169-C-T
• rs1225040813
• NM_001433.5:c.2287G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_001433.5(ERN1):​c.2287G>A​(p.Val763Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000748 in 1,603,590 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: ERN1 NM_001433.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.72

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 -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.33615017).
• BS2: High AC in GnomAdExome4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ERN1	NM_001433.5	c.2287G>A	p.Val763Ile	missense_variant	Exon 18 of 22	ENST00000433197.4	NP_001424.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ERN1	ENST00000433197.4	c.2287G>A	p.Val763Ile	missense_variant	Exon 18 of 22	1	NM_001433.5	ENSP00000401445.2
ERN1	ENST00000680433.1	c.2287G>A	p.Val763Ile	missense_variant	Exon 18 of 20			ENSP00000506094.1
ERN1	ENST00000680625.1	n.2205G>A		non_coding_transcript_exon_variant	Exon 17 of 21

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152232 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000810 AC: 2 AN: 246868 AF XY: 0.00000746

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000178

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000620 AC: 9 AN: 1451242 Hom.: 0 Cov.: 30 AF XY: 0.00000555 AC XY: 4 AN XY: 720322

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 33196

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 44368

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 25980

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39314

Gnomad4 SAS exome AF: 0.0000117 AC: 1 AN: 85706

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53244

Gnomad4 NFE exome AF: 0.00000634 AC: 7 AN: 1103922

Gnomad4 Remaining exome AF: 0.0000167 AC: 1 AN: 59794

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152348 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74486

Gnomad4 AFR AF: 0.0000241 AC: 0.0000240535 AN: 0.0000240535

Gnomad4 AMR AF: 0.00 AC: 0 AN: 0

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.0000294 AC: 0.0000293945 AN: 0.0000293945

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 30, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2287G>A (p.V763I) alteration is located in exon 18 (coding exon 18) of the ERN1 gene. This alteration results from a G to A substitution at nucleotide position 2287, causing the valine (V) at amino acid position 763 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	0.0024	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.072	T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.34	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.1	L
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.72	N
REVEL	Benign	0.19
Sift	Uncertain	0.024	D
Sift4G	Benign	0.13	T
Polyphen		0.61	P
Vest4		0.41
MutPred		0.43		Loss of helix (P = 0.1299);
MVP		0.55
MPC		0.86
ClinPred		0.64	D
GERP RS		6.0
Varity_R		0.57
gMVP		0.65
Mutation Taster		=51/49	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

Publications

LitVar

Other links and lift over

dbSNP: rs1225040813; hg19: chr17-62126529; COSMIC: COSV104715191; COSMIC: COSV104715191;