3-5188206-C-T

Position:

• chr3-5188206-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_014674.3(EDEM1):​c.401C>T​(p.Ala134Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000028 in 1,429,862 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: EDEM1 NM_014674.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.33

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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EDEM1	NM_014674.3	c.401C>T	p.Ala134Val	missense_variant	1/12	ENST00000256497.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EDEM1	ENST00000256497.9	c.401C>T	p.Ala134Val	missense_variant	1/12	1	NM_014674.3	P1
	ENST00000600805.2	n.93G>A		non_coding_transcript_exon_variant	1/1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000998 AC: 2 AN: 200488 Hom.: 0 AF XY: 0.00000910 AC XY: 1 AN XY: 109894

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000113

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000390

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000280 AC: 4 AN: 1429862 Hom.: 0 Cov.: 31 AF XY: 0.00000423 AC XY: 3 AN XY: 709810

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000273

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Uncertain	0.066	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.065	T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.18
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.50	D
MetaRNN	Uncertain	0.56	D
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	0.90	L
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-0.070	N
REVEL	Uncertain	0.40
Sift	Benign	0.20	T
Sift4G	Benign	0.80	T
Polyphen		0.22	B
Vest4		0.66
MutPred		0.60		Loss of methylation at R135 (P = 0.093);
MVP		0.85
MPC		0.34
ClinPred		0.33	T
GERP RS		2.4
Varity_R		0.18
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1196598925; hg19: chr3-5229891;