NM_025191.4:c.2431G>T

Variant names:

• chr1-184694431-C-A
• rs765435034
• NM_025191.4:c.2431G>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BS1_Supporting

The NM_025191.4(EDEM3):​c.2431G>T​(p.Asp811Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.0000261 in 1,608,268 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000028 (0 hom.)
• Consequence: EDEM3 NM_025191.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 3.64
• 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: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.19759893).
• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.0000282 (41/1456212) while in subpopulation SAS AF = 0.000279 (24/86070). AF 95% confidence interval is 0.000192. There are 0 homozygotes in GnomAdExome4. There are 28 alleles in the male GnomAdExome4 subpopulation. Median coverage is 35. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.2431G>T	p.Asp811Tyr	missense	Exon 20 of 20	NP_079467.3
	EDEM3	NM_001319960.2		c.2479G>T	p.Asp827Tyr	missense	Exon 21 of 21	NP_001306889.1	A0A8J8YX80
	EDEM3	NR_135118.2		n.2710G>T		non_coding_transcript_exon	Exon 21 of 21

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EDEM3	ENST00000318130.13	TSL:1 MANE Select	c.2431G>T	p.Asp811Tyr	missense	Exon 20 of 20	ENSP00000318147.7	Q9BZQ6-1
	EDEM3	ENST00000367512.8	TSL:1	c.2479G>T	p.Asp827Tyr	missense	Exon 21 of 21	ENSP00000356482.4	A0A8J8YX80
	EDEM3	ENST00000439962.1	TSL:1	n.775G>T		non_coding_transcript_exon	Exon 6 of 8	ENSP00000390536.1	H0Y498

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152056 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000285 AC: 7 AN: 245288 AF XY: 0.0000451

Gnomad AFR exome AF: 0.00

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: 0.0000272

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000282 AC: 41 AN: 1456212 Hom.: 0 Cov.: 35 AF XY: 0.0000387 AC XY: 28 AN XY: 723980

African (AFR) AF: 0.00 AC: 0 AN: 33350

American (AMR) AF: 0.00 AC: 0 AN: 44396

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25964

East Asian (EAS) AF: 0.00 AC: 0 AN: 39586

South Asian (SAS) AF: 0.000279 AC: 24 AN: 86070

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51860

Middle Eastern (MID) AF: 0.000176 AC: 1 AN: 5694

European-Non Finnish (NFE) AF: 0.00000721 AC: 8 AN: 1109132

Other (OTH) AF: 0.000133 AC: 8 AN: 60160

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152056 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74276

African (AFR) AF: 0.00 AC: 0 AN: 41434

American (AMR) AF: 0.00 AC: 0 AN: 15234

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67968

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

Alfa AF: 0.0000508 Hom.: 0

Bravo AF: 0.00000756

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.0000247 AC: 3

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
1	-	-	Short stature (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.011	T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.31	T
MutationAssessor	Benign	1.0	L
PhyloP100		3.6
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.22
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.020	D
Polyphen		0.91	P
Vest4		0.22
MutPred		0.12		Gain of phosphorylation at D811 (P = 0.0174)
MVP		0.83
MPC		0.43
ClinPred		0.30	T
GERP RS		5.4
Varity_R		0.21
gMVP		0.54
Mutation Taster		=81/19	disease causing (ClinVar)

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: rs765435034; hg19: chr1-184663565; COSMIC: COSV58925847; COSMIC: COSV58925847;