Variant 17-64044134-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4BS2

The NM_001433.5(ERN1):c.2788G>A(p.Val930Met) variant causes a missense change. The variant allele was found at a frequency of 0.000106 in 1,607,396 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 0.00022 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000093 ( 0 hom. )

Consequence

ERN1
NM_001433.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.87

Variant links:

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]

ERN1 links:

ERN1 (HGNC:):

ERN1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.29276076).

BS2

High AC in GnomAd4 at 34 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ERN1	NM_001433.5 linkuse as main transcript	c.2788G>A	p.Val930Met	missense_variant	22/22	ENST00000433197.4	NP_001424.3	O75460-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ERN1	ENST00000433197.4 linkuse as main transcript	c.2788G>A	p.Val930Met	missense_variant	22/22	1	NM_001433.5	ENSP00000401445.2	O75460-1
ERN1	ENST00000680433.1 linkuse as main transcript	c.*1160G>A		3_prime_UTR_variant	20/20			ENSP00000506094.1	A0A7P0TAB0
ERN1	ENST00000680625.1 linkuse as main transcript	n.2706G>A		non_coding_transcript_exon_variant	21/21

Frequencies

GnomAD3 genomes

AF:

0.000224

AC:

AN:

152106

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000266

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:

0.000338

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000905

AC:

AN:

243180

Hom.:

AF XY:

0.000106

AC XY:

AN XY:

131990

show subpopulations

Gnomad AFR exome

AF:

0.000196

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000172

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000935

AC:

136

AN:

1455290

Hom.:

Cov.:

AF XY:

0.0000940

AC XY:

AN XY:

723444

show subpopulations

Gnomad4 AFR exome

AF:

0.000450

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000104

Gnomad4 OTH exome

AF:

0.0000999

GnomAD4 genome

AF:

0.000224

AC:

AN:

152106

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74286

show subpopulations

Gnomad4 AFR

AF:

0.000266

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000338

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000211

Hom.:

Bravo

AF:

0.000185

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000357

AC:

ExAC

AF:

0.000107

AC:

EpiCase

AF:

0.000111

EpiControl

AF:

0.000120

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 04, 2022

The c.2788G>A (p.V930M) alteration is located in exon 22 (coding exon 22) of the ERN1 gene. This alteration results from a G to A substitution at nucleotide position 2788, causing the valine (V) at amino acid position 930 to be replaced by a methionine (M). 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

Pathogenic

0.70

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.37

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.13

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.83

M_CAP

Benign

0.043

MetaRNN

Benign

0.29

MetaSVM

Benign

-0.89

MutationAssessor

Uncertain

2.6

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-2.3

REVEL

Benign

0.19

Sift

Uncertain

0.012

Sift4G

Uncertain

0.0060

Polyphen

1.0

Vest4

0.28

MVP

0.47

MPC

1.1

ClinPred

0.35

GERP RS

4.3

Varity_R

0.37

gMVP

0.67

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over