Variant 17-64044184-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_001433.5(ERN1):c.2738A>G(p.Glu913Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000943 in 1,558,248 control chromosomes in the GnomAD database, including 4 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00041 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0010 ( 4 hom. )

Consequence

ERN1
NM_001433.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.98

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High AC in GnomAd4 at 62 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ERN1	NM_001433.5 linkuse as main transcript	c.2738A>G	p.Glu913Gly	missense_variant	22/22	ENST00000433197.4	NP_001424.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ERN1	ENST00000433197.4 linkuse as main transcript	c.2738A>G	p.Glu913Gly	missense_variant	22/22	1	NM_001433.5	ENSP00000401445	P1	O75460-1
ERN1	ENST00000680433.1 linkuse as main transcript	c.*1110A>G		3_prime_UTR_variant	20/20			ENSP00000506094
ERN1	ENST00000680625.1 linkuse as main transcript	n.2656A>G		non_coding_transcript_exon_variant	21/21

Frequencies

GnomAD3 genomes

AF:

0.000408

AC:

AN:

152062

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

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:

0.000809

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000597

AC:

126

AN:

211158

Hom.:

AF XY:

0.000562

AC XY:

AN XY:

113816

show subpopulations

Gnomad AFR exome

AF:

0.000206

Gnomad AMR exome

AF:

0.000463

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000153

Gnomad NFE exome

AF:

0.00104

Gnomad OTH exome

AF:

0.000998

GnomAD4 exome

AF:

0.00100

AC:

1408

AN:

1406068

Hom.:

Cov.:

AF XY:

0.000967

AC XY:

671

AN XY:

693820

show subpopulations

Gnomad4 AFR exome

AF:

0.000281

Gnomad4 AMR exome

AF:

0.000414

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000387

Gnomad4 NFE exome

AF:

0.00122

Gnomad4 OTH exome

AF:

0.00107

GnomAD4 genome

AF:

0.000407

AC:

AN:

152180

Hom.:

Cov.:

AF XY:

0.000390

AC XY:

AN XY:

74402

show subpopulations

Gnomad4 AFR

AF:

0.000145

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000809

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00110

Hom.:

Bravo

AF:

0.000446

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00109

AC:

ExAC

AF:

0.000563

AC:

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

Apr 25, 2022

The c.2738A>G (p.E913G) alteration is located in exon 22 (coding exon 22) of the ERN1 gene. This alteration results from a A to G substitution at nucleotide position 2738, causing the glutamic acid (E) at amino acid position 913 to be replaced by a glycine (G). 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

0.96

BayesDel_addAF

Benign

-0.082

BayesDel_noAF

Uncertain

0.090

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.44

Eigen

Pathogenic

0.76

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

M_CAP

Benign

0.058

MetaRNN

Uncertain

0.53

MetaSVM

Uncertain

-0.069

MutationAssessor

Pathogenic

3.6

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.56

PROVEAN

Pathogenic

-6.6

REVEL

Pathogenic

0.66

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0020

Polyphen

0.99

Vest4

0.69

MVP

0.72

MPC

1.3

ClinPred

0.61

GERP RS

5.2

Varity_R

0.90

gMVP

0.56

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

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