3-5188163-G-A

Variant names:

• chr3-5188163-G-A
• rs758507201
• NM_014674.3:c.358G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014674.3(EDEM1):​c.358G>A​(p.Gly120Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000043 in 1,396,778 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G120C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000043 (0 hom.)
• Consequence: EDEM1 NM_014674.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.179
• Publications: 0 publications found

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]

ENSG00000233912 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11014661).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014674.3. 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
	EDEM1	NM_014674.3	MANE Select	c.358G>A	p.Gly120Ser	missense	Exon 1 of 12	NP_055489.1	Q92611-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EDEM1	ENST00000256497.9	TSL:1 MANE Select	c.358G>A	p.Gly120Ser	missense	Exon 1 of 12	ENSP00000256497.4	Q92611-1
	EDEM1	ENST00000443790.1	TSL:2	n.*219G>A		non_coding_transcript_exon	Exon 1 of 2	ENSP00000394615.1	F8WE67
	EDEM1	ENST00000465187.1	TSL:4	n.358G>A		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000430 AC: 6 AN: 1396778 Hom.: 0 Cov.: 31 AF XY: 0.00000869 AC XY: 6 AN XY: 690448

African (AFR) AF: 0.00 AC: 0 AN: 30028

American (AMR) AF: 0.00 AC: 0 AN: 35730

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24884

East Asian (EAS) AF: 0.00 AC: 0 AN: 34720

South Asian (SAS) AF: 0.0000763 AC: 6 AN: 78616

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48590

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5676

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1080606

Other (OTH) AF: 0.00 AC: 0 AN: 57928

GnomAD4 genome Cov.: 32

Asia WGS AF: 0.000291 AC: 1 AN: 3456

ClinVar

ClinVar submissions

Significance: Uncertain significance

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	0.078
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	16
DANN	Benign	0.96
DEOGEN2	Benign	0.031	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.67	T
M_CAP	Pathogenic	0.87	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	-0.20	N
PhyloP100		0.18
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	0.070	N
REVEL	Benign	0.21
Sift	Benign	0.28	T
Sift4G	Benign	0.44	T
Polyphen		0.0040	B
Vest4		0.14
MutPred		0.29		Gain of phosphorylation at G120 (P = 0.023)
MVP		0.71
MPC		0.26
ClinPred		0.086	T
GERP RS		-3.6
PromoterAI		-0.073	Neutral
Varity_R		0.059
gMVP		0.63
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs758507201; hg19: chr3-5229848;