1-184706774-T-A

Variant names:

• chr1-184706774-T-A
• rs373286484
• NM_025191.4:c.2072A>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_025191.4(EDEM3):​c.2072A>T​(p.Asn691Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. N691S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: EDEM3 NM_025191.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.22
• Publications: 2 publications found

Genes affected

EDEM3 (HGNC:16787): (ER degradation enhancing alpha-mannosidase like protein 3) Quality control in the endoplasmic reticulum (ER) ensures that only properly folded proteins are retained in the cell through recognition and degradation of misfolded or unassembled proteins. EDEM3 belongs to a group of proteins that accelerate degradation of misfolded glycoproteins in the ER (Hirao et al., 2006 [PubMed 16431915]).[supplied by OMIM, Mar 2008]

EDEM3 Gene-Disease associations (from GenCC):

• congenital disorder of glycosylation, type 2v

  Inheritance: AR Classification: STRONG Submitted by: ClinGen, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_025191.4. 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
	EDEM3	NM_025191.4	MANE Select	c.2072A>T	p.Asn691Ile	missense	Exon 18 of 20	NP_079467.3
	EDEM3	NM_001319960.2		c.2072A>T	p.Asn691Ile	missense	Exon 18 of 21	NP_001306889.1	A0A8J8YX80
	EDEM3	NR_135118.2		n.2303A>T		non_coding_transcript_exon	Exon 18 of 21

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EDEM3	ENST00000318130.13	TSL:1 MANE Select	c.2072A>T	p.Asn691Ile	missense	Exon 18 of 20	ENSP00000318147.7	Q9BZQ6-1
	EDEM3	ENST00000367512.8	TSL:1	c.2072A>T	p.Asn691Ile	missense	Exon 18 of 21	ENSP00000356482.4	A0A8J8YX80
	EDEM3	ENST00000439962.1	TSL:1	n.416A>T		non_coding_transcript_exon	Exon 4 of 8	ENSP00000390536.1	H0Y498

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250900 AF XY: 0.00

Gnomad AFR exome AF: 0.0000615

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 Cov.: 32

GnomAD4 genome Cov.: 32

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.44
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.14	T
Eigen	Benign	0.080
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.0081	T
MetaRNN	Uncertain	0.43	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L
PhyloP100		3.2
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-3.4	D
REVEL	Benign	0.12
Sift	Benign	0.10	T
Sift4G	Benign	0.14	T
Polyphen		0.47	P
Vest4		0.69
MVP		0.23
MPC		0.28
ClinPred		0.68	D
GERP RS		4.7
Varity_R		0.40
gMVP		0.72
Mutation Taster		=65/35	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs373286484; hg19: chr1-184675908;