Genetic Variant EDEM1:p.Leu12Ile (chr3-5187839-C-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_014674.3(EDEM1):c.34C>A(p.Leu12Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000695 in 1,438,838 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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. L12F) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

EDEM1
NM_014674.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.18

Publications

0 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 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.29163888).

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.34C>A	p.Leu12Ile	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.34C>A	p.Leu12Ile	missense	Exon 1 of 12	ENSP00000256497.4	Q92611-1
EDEM1	ENST00000443790.1	TSL:2	n.57C>A		non_coding_transcript_exon	Exon 1 of 2	ENSP00000394615.1	F8WE67
EDEM1	ENST00000465187.1	TSL:4	n.34C>A		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.95e-7

AC:

AN:

1438838

Hom.:

Cov.:

AF XY:

0.00000140

AC XY:

AN XY:

715716

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000321

AC:

AN:

31126

American (AMR)

AF:

0.00

AC:

AN:

42276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25518

East Asian (EAS)

AF:

0.00

AC:

AN:

37092

South Asian (SAS)

AF:

0.00

AC:

AN:

83808

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52182

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5160

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1102210

Other (OTH)

AF:

0.00

AC:

AN:

59466

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

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.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.0077

BayesDel_noAF

Benign

-0.25

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.065

Eigen

Benign

-0.16

Eigen_PC

Benign

-0.030

FATHMM_MKL

Benign

0.58

LIST_S2

Benign

0.79

M_CAP

Pathogenic

0.95

MetaRNN

Benign

0.29

MetaSVM

Benign

-0.31

MutationAssessor

Benign

1.4

PhyloP100

1.2

PrimateAI

Pathogenic

0.89

PROVEAN

Benign

0.030

REVEL

Benign

0.18

Sift

Benign

0.10

Sift4G

Benign

0.32

Polyphen

0.043

Vest4

0.36

MutPred

0.23

Gain of MoRF binding (P = 0.0933)

MVP

0.91

MPC

0.30

ClinPred

0.76

GERP RS

4.3

PromoterAI

0.039

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.9

Varity_R

0.21

gMVP

0.37

Mutation Taster

=86/14

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