rs377481139

Variant names:

• chr3-5187839-C-T
• rs377481139
• NM_014674.3:c.34C>T

Your query was ambiguous. Multiple possible variants found:

• chr3-5187839-C-T
• chr3-5187839-C-A
• chr3-5187839-C-G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_014674.3(EDEM1):​c.34C>T​(p.Leu12Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000528 in 1,590,974 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: 32)
  • Exomes 𝑓: 0.000058 (0 hom.)
• Consequence: EDEM1 NM_014674.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.18
• Publications: 1 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33746654).

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.34C>T	p.Leu12Phe	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.34C>T	p.Leu12Phe	missense	Exon 1 of 12	ENSP00000256497.4	Q92611-1
	EDEM1	ENST00000443790.1	TSL:2	n.57C>T		non_coding_transcript_exon	Exon 1 of 2	ENSP00000394615.1	F8WE67
	EDEM1	ENST00000465187.1	TSL:4	n.34C>T		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152136 Hom.: 0 Cov.: 32

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: 0.0000362 AC: 8 AN: 221294 AF XY: 0.0000574

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: 0.0000811

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000577 AC: 83 AN: 1438838 Hom.: 0 Cov.: 30 AF XY: 0.0000545 AC XY: 39 AN XY: 715716

African (AFR) AF: 0.00 AC: 0 AN: 31126

American (AMR) AF: 0.00 AC: 0 AN: 42276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25518

East Asian (EAS) AF: 0.00 AC: 0 AN: 37092

South Asian (SAS) AF: 0.00 AC: 0 AN: 83808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52182

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5160

European-Non Finnish (NFE) AF: 0.0000735 AC: 81 AN: 1102210

Other (OTH) AF: 0.0000336 AC: 2 AN: 59466

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152136 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74322

African (AFR) AF: 0.00 AC: 0 AN: 41450

American (AMR) AF: 0.00 AC: 0 AN: 15288

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68002

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000997 Hom.: 0

Bravo AF: 0.0000302

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000330 AC: 4

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	0.089
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.065	T
Eigen	Benign	0.088
Eigen_PC	Benign	0.15
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.82	T
M_CAP	Pathogenic	0.98	D
MetaRNN	Benign	0.34	T
MetaSVM	Uncertain	0.015	D
MutationAssessor	Benign	1.4	L
PhyloP100		1.2
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.14	N
REVEL	Benign	0.28
Sift	Uncertain	0.025	D
Sift4G	Benign	0.063	T
Polyphen		0.61	P
Vest4		0.35
MVP		0.99
MPC		0.48
ClinPred		0.26	T
GERP RS		4.3
PromoterAI		0.0088	Neutral
Varity_R		0.25
gMVP		0.55
Mutation Taster		=83/17	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: rs377481139; hg19: chr3-5229524;