dbSNP rs1271865128: EDEM1:p.Pro59Arg (chr3-5187981-C-G) – 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.176C>G(p.Pro59Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000721 in 1,387,902 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P59L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

EDEM1
NM_014674.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.243

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=0.23770228).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EDEM1	NM_014674.3 link	c.176C>G	p.Pro59Arg	missense_variant	Exon 1 of 12	ENST00000256497.9	NP_055489.1	Q92611-1A0A024R2D5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EDEM1	ENST00000256497.9 link	c.176C>G	p.Pro59Arg	missense_variant	Exon 1 of 12	1	NM_014674.3	ENSP00000256497.4		Q92611-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.21e-7

AC:

AN:

1387902

Hom.:

Cov.:

AF XY:

0.00000146

AC XY:

AN XY:

686106

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29536

American (AMR)

AF:

0.00

AC:

AN:

35024

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24738

East Asian (EAS)

AF:

0.00

AC:

AN:

34188

South Asian (SAS)

AF:

0.00

AC:

AN:

78784

European-Finnish (FIN)

AF:

0.00

AC:

AN:

45496

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4194

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1078352

Other (OTH)

AF:

0.0000174

AC:

AN:

57590

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.090

BayesDel_noAF

Benign

-0.37

CADD

Benign

(source)

DANN

Benign

0.49

DEOGEN2

Benign

0.038

Eigen

Benign

-0.74

Eigen_PC

Benign

-0.76

FATHMM_MKL

Benign

0.079

LIST_S2

Benign

0.42

M_CAP

Pathogenic

0.95

MetaRNN

Benign

0.24

MetaSVM

Benign

-0.78

MutationAssessor

Benign

0.69

PhyloP100

0.24

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

-0.37

REVEL

Benign

0.23

Sift

Benign

0.11

Sift4G

Benign

0.75

Polyphen

0.26

Vest4

0.082

MutPred

0.24

Gain of methylation at P59 (P = 0.031);

MVP

0.95

MPC

0.38

ClinPred

0.15

GERP RS

4.2

PromoterAI

-0.13

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.3

Varity_R

0.063

gMVP

0.61

Mutation Taster

=91/9

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

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rs1271865128

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over