NM_018217.3:c.1585G>A

Variant names:

• chr20-35115585-C-T
• rs747266455
• NM_018217.3:c.1585G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

The NM_018217.3(EDEM2):​c.1585G>A​(p.Ala529Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000018 in 1,613,720 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A529E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00011 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: EDEM2 NM_018217.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.449
• Publications: 0 publications found

Genes affected

EDEM2 (HGNC:15877): (ER degradation enhancing alpha-mannosidase like protein 2) In the endoplasmic reticulum (ER), misfolded proteins are retrotranslocated to the cytosol and degraded by the proteasome in a process known as ER-associated degradation (ERAD). EDEM2 belongs to a family of proteins involved in ERAD of glycoproteins (Mast et al., 2005 [PubMed 15537790]).[supplied by OMIM, Mar 2008]

MMP24-AS1-EDEM2 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.017775565).
• BP6: Variant 20-35115585-C-T is Benign according to our data. Variant chr20-35115585-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2362848.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018217.3. 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
	EDEM2	NM_018217.3	MANE Select	c.1585G>A	p.Ala529Thr	missense	Exon 11 of 11	NP_060687.2	Q9BV94-1
	EDEM2	NM_001145025.2		c.1474G>A	p.Ala492Thr	missense	Exon 10 of 10	NP_001138497.1	Q9BV94-2
	MMP24-AS1-EDEM2	NM_001355008.2		c.1462G>A	p.Ala488Thr	missense	Exon 15 of 15	NP_001341937.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EDEM2	ENST00000374492.8	TSL:1 MANE Select	c.1585G>A	p.Ala529Thr	missense	Exon 11 of 11	ENSP00000363616.3	Q9BV94-1
	EDEM2	ENST00000374491.3	TSL:1	c.1474G>A	p.Ala492Thr	missense	Exon 10 of 10	ENSP00000363615.2	Q9BV94-2
	EDEM2	ENST00000881595.1		c.1633G>A	p.Ala545Thr	missense	Exon 12 of 12	ENSP00000551654.1

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 151826 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000413

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000318 AC: 8 AN: 251464 AF XY: 0.0000368

Gnomad AFR exome AF: 0.000492

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: 0.00000821 AC: 12 AN: 1461894 Hom.: 0 Cov.: 31 AF XY: 0.00000688 AC XY: 5 AN XY: 727248

African (AFR) AF: 0.000358 AC: 12 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome AF: 0.000112 AC: 17 AN: 151826 Hom.: 1 Cov.: 32 AF XY: 0.000135 AC XY: 10 AN XY: 74150

African (AFR) AF: 0.000413 AC: 17 AN: 41154

American (AMR) AF: 0.00 AC: 0 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68010

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.000142 Hom.: 0

ExAC AF: 0.0000412 AC: 5

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	0.15
DANN	Benign	0.71
DEOGEN2	Benign	0.0073	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.042	N
LIST_S2	Benign	0.60	T
M_CAP	Benign	0.0060	T
MetaRNN	Benign	0.018	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N
PhyloP100		-0.45
PrimateAI	Benign	0.22	T
PROVEAN	Benign	0.050	N
REVEL	Benign	0.021
Sift	Benign	0.82	T
Sift4G	Benign	0.63	T
Polyphen		0.0	B
Vest4		0.017
MutPred		0.12		Gain of phosphorylation at A529 (P = 0.002)
MVP		0.19
MPC		0.32
ClinPred		0.012	T
GERP RS		-5.6
Varity_R		0.017
gMVP		0.21
Mutation Taster		=89/11	polymorphism

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

Other links and lift over

dbSNP: rs747266455; hg19: chr20-33703388;