Genetic Variant EDEM3:p.Pro746Ser (chr1-184702964-G-A) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_ModerateBS1BS2

The NM_025191.4(EDEM3):c.2236C>T(p.Pro746Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.016 in 1,611,476 control chromosomes in the GnomAD database, including 255 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.012 ( 21 hom., cov: 32)

Exomes 𝑓: 0.016 ( 234 hom. )

Consequence

EDEM3
NM_025191.4 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 7.96

Variant links:

Genes affected

EDEM3 (HGNC:16787): (ER degradation enhancing alpha-mannosidase like protein 3) Quality control in the endoplasmic reticulum (ER) ensures that only properly folded proteins are retained in the cell through recognition and degradation of misfolded or unassembled proteins. EDEM3 belongs to a group of proteins that accelerate degradation of misfolded glycoproteins in the ER (Hirao et al., 2006 [PubMed 16431915]).[supplied by OMIM, Mar 2008]

EDEM3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP6

Variant 1-184702964-G-A is Benign according to our data. Variant chr1-184702964-G-A is described in ClinVar as [Benign]. Clinvar id is 3068615.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0115 (1756/152102) while in subpopulation NFE AF= 0.0179 (1217/67986). AF 95% confidence interval is 0.0171. There are 21 homozygotes in gnomad4. There are 858 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EDEM3	NM_025191.4 link	c.2236C>T	p.Pro746Ser	missense_variant	Exon 19 of 20	ENST00000318130.13	NP_079467.3	Q9BZQ6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EDEM3	ENST00000318130.13 link	c.2236C>T	p.Pro746Ser	missense_variant	Exon 19 of 20	1	NM_025191.4	ENSP00000318147.7		Q9BZQ6-1

Frequencies

GnomAD3 genomes

AF:

0.0116

AC:

1757

AN:

151984

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00249

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.00806

Gnomad ASJ

AF:

0.0256

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00436

Gnomad FIN

AF:

0.0161

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0179

Gnomad OTH

AF:

0.0125

GnomAD3 exomes

AF:

0.0118

AC:

2927

AN:

248222

Hom.:

AF XY:

0.0118

AC XY:

1582

AN XY:

134242

show subpopulations

Gnomad AFR exome

AF:

0.00293

Gnomad AMR exome

AF:

0.00422

Gnomad ASJ exome

AF:

0.0192

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00672

Gnomad FIN exome

AF:

0.0175

Gnomad NFE exome

AF:

0.0168

Gnomad OTH exome

AF:

0.0122

GnomAD4 exome

AF:

0.0165

AC:

24077

AN:

1459374

Hom.:

234

Cov.:

AF XY:

0.0162

AC XY:

11755

AN XY:

726044

show subpopulations

Gnomad4 AFR exome

AF:

0.00268

Gnomad4 AMR exome

AF:

0.00450

Gnomad4 ASJ exome

AF:

0.0203

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00673

Gnomad4 FIN exome

AF:

0.0166

Gnomad4 NFE exome

AF:

0.0189

Gnomad4 OTH exome

AF:

0.0134

GnomAD4 genome

AF:

0.0115

AC:

1756

AN:

152102

Hom.:

Cov.:

AF XY:

0.0115

AC XY:

858

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.00248

Gnomad4 AMR

AF:

0.00805

Gnomad4 ASJ

AF:

0.0256

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00437

Gnomad4 FIN

AF:

0.0161

Gnomad4 NFE

AF:

0.0179

Gnomad4 OTH

AF:

0.0123

Alfa

AF:

0.0167

Hom.:

Bravo

AF:

0.0102

TwinsUK

AF:

0.0183

AC:

ALSPAC

AF:

0.0202

AC:

ESP6500AA

AF:

0.00272

AC:

ESP6500EA

AF:

0.0165

AC:

142

ExAC

AF:

0.0116

AC:

1404

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.0130

EpiControl

AF:

0.0146

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Congenital disorder of glycosylation, type 2v

Benign:1

May 04, 2023

Molecular Genetics, Royal Melbourne Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

European Non-Finnish population allele frequency is 1.620% (rs78444298, 2196/127710 alleles, 30 homozygotes in gnomAD v2.1). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.5.1, this variant is classified as BENIGN. Following criteria are met: BA1 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.85

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.40

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.12

T;.

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

D;D

MetaRNN

Benign

0.0096

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.6

L;.

PrimateAI

Uncertain

0.76

PROVEAN

Uncertain

-3.8

D;D

REVEL

Benign

0.24

Sift

Benign

0.18

T;T

Sift4G

Benign

0.24

T;T

Polyphen

0.75

P;.

Vest4

0.43

MPC

0.41

ClinPred

0.020

GERP RS

5.2

Varity_R

0.28

gMVP

0.76

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.26

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.26

Position offset: 32

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