Genetic Variant EDEM1:p.Arg45Ser (chr3-5187938-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_014674.3(EDEM1):c.133C>A(p.Arg45Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000021 in 1,431,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R45C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

EDEM1
NM_014674.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.396

Publications

1 publications found

Variant links:

Genes affected

EDEM1 (HGNC:18967): (ER degradation enhancing alpha-mannosidase like protein 1) Enables mannosyl-oligosaccharide 1,2-alpha-mannosidase activity and misfolded protein binding activity. Involved in mannose trimming involved in glycoprotein ERAD pathway; positive regulation of retrograde protein transport, ER to cytosol; and protein targeting to ER. Located in aggresome and endoplasmic reticulum quality control compartment. [provided by Alliance of Genome Resources, Apr 2022]

EDEM1 links:

ENSG00000233912 (HGNC:):

ENSG00000233912 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.16320398).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014674.3. 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
	EDEM1	NM_014674.3	MANE Select	c.133C>A	p.Arg45Ser	missense	Exon 1 of 12	NP_055489.1	Q92611-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EDEM1	ENST00000256497.9	TSL:1 MANE Select	c.133C>A	p.Arg45Ser	missense	Exon 1 of 12	ENSP00000256497.4	Q92611-1
EDEM1	ENST00000443790.1	TSL:2	n.156C>A		non_coding_transcript_exon	Exon 1 of 2	ENSP00000394615.1	F8WE67
EDEM1	ENST00000465187.1	TSL:4	n.133C>A		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

191448

AF XY:

0.00

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000210

AC:

AN:

1431888

Hom.:

Cov.:

AF XY:

0.00000281

AC XY:

AN XY:

710982

show subpopulations

African (AFR)

AF:

0.0000315

AC:

AN:

31790

American (AMR)

AF:

0.00

AC:

AN:

41078

Ashkenazi Jewish (ASJ)

AF:

0.0000391

AC:

AN:

25600

East Asian (EAS)

AF:

0.00

AC:

AN:

37600

South Asian (SAS)

AF:

0.00

AC:

AN:

82788

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48822

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4378

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1100670

Other (OTH)

AF:

0.0000169

AC:

AN:

59162

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.074

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

DANN

Benign

0.82

DEOGEN2

Benign

0.047

Eigen

Benign

-0.76

Eigen_PC

Benign

-0.72

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.62

M_CAP

Pathogenic

0.82

MetaRNN

Benign

0.16

MetaSVM

Benign

-0.86

MutationAssessor

Benign

0.55

PhyloP100

0.40

PrimateAI

Pathogenic

0.86

PROVEAN

Benign

-0.060

REVEL

Benign

0.099

Sift

Benign

0.19

Sift4G

Benign

0.43

Polyphen

0.0070

Vest4

0.23

MutPred

0.24

Gain of phosphorylation at R45 (P = 0.0337)

MVP

0.90

MPC

0.29

ClinPred

0.090

GERP RS

1.3

PromoterAI

-0.015

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.12

gMVP

0.32

Mutation Taster

=78/22

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over