Genetic Variant EDEM1:c.583-54C>T (chr3-5199538-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_014674.3(EDEM1):c.583-54C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.961 in 1,364,250 control chromosomes in the GnomAD database, including 630,803 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.93 ( 66673 hom., cov: 32)

Exomes 𝑓: 0.96 ( 564130 hom. )

Consequence

EDEM1
NM_014674.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.76

Publications

3 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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.98).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.969 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EDEM1	NM_014674.3 link	c.583-54C>T		intron_variant	Intron 2 of 11	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.583-54C>T		intron_variant	Intron 2 of 11	1	NM_014674.3	ENSP00000256497.4		Q92611-1

Frequencies

GnomAD3 genomes

AF:

0.934

AC:

142106

AN:

152148

Hom.:

66633

Cov.:

show subpopulations

Gnomad AFR

AF:

0.842

Gnomad AMI

AF:

0.933

Gnomad AMR

AF:

0.966

Gnomad ASJ

AF:

0.970

Gnomad EAS

AF:

0.936

Gnomad SAS

AF:

0.881

Gnomad FIN

AF:

0.988

Gnomad MID

AF:

0.940

Gnomad NFE

AF:

0.975

Gnomad OTH

AF:

0.956

GnomAD4 exome

AF:

0.964

AC:

1168655

AN:

1211984

Hom.:

564130

AF XY:

0.963

AC XY:

589700

AN XY:

612656

show subpopulations

African (AFR)

AF:

0.831

AC:

23424

AN:

28182

American (AMR)

AF:

0.981

AC:

39499

AN:

40276

Ashkenazi Jewish (ASJ)

AF:

0.967

AC:

22810

AN:

23600

East Asian (EAS)

AF:

0.945

AC:

35938

AN:

38012

South Asian (SAS)

AF:

0.896

AC:

69507

AN:

77584

European-Finnish (FIN)

AF:

0.986

AC:

51192

AN:

51932

Middle Eastern (MID)

AF:

0.973

AC:

5077

AN:

5220

European-Non Finnish (NFE)

AF:

0.974

AC:

871619

AN:

895292

Other (OTH)

AF:

0.956

AC:

49589

AN:

51886

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

1580

3160

4741

6321

7901

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16076

32152

48228

64304

80380

<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

AF:

0.934

AC:

142201

AN:

152266

Hom.:

66673

Cov.:

AF XY:

0.933

AC XY:

69475

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.842

AC:

34956

AN:

41510

American (AMR)

AF:

0.966

AC:

14785

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.970

AC:

3367

AN:

3472

East Asian (EAS)

AF:

0.936

AC:

4852

AN:

5186

South Asian (SAS)

AF:

0.881

AC:

4242

AN:

4816

European-Finnish (FIN)

AF:

0.988

AC:

10488

AN:

10616

Middle Eastern (MID)

AF:

0.939

AC:

276

AN:

294

European-Non Finnish (NFE)

AF:

0.975

AC:

66373

AN:

68044

Other (OTH)

AF:

0.951

AC:

2011

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

467

934

1400

1867

2334

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

908

1816

2724

3632

4540

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.927

Hom.:

21072

Bravo

AF:

0.930

Asia WGS

AF:

0.892

AC:

3104

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.98

CADD

Benign

0.024

(source)

DANN

Benign

0.65

PhyloP100

-2.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over