chr3-5187981-C-T

Variant names:

• chr3-5187981-C-T
• rs1271865128
• NM_014674.3:c.176C>T

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.176C>T​(p.Pro59Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000584 in 1,539,908 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 0.000020 (0 hom., 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: 0.243

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=0.25310993).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EDEM1	NM_014674.3	c.176C>T	p.Pro59Leu	missense_variant	Exon 1 of 12	ENST00000256497.9	NP_055489.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EDEM1	ENST00000256497.9	c.176C>T	p.Pro59Leu	missense_variant	Exon 1 of 12	1	NM_014674.3	ENSP00000256497.4

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152006 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: 0.0000442

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000758 AC: 1 AN: 131938 AF XY: 0.0000137

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000443

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 AF: 0.00000432 AC: 6 AN: 1387902 Hom.: 0 Cov.: 31 AF XY: 0.00000729 AC XY: 5 AN XY: 686106

African (AFR) AF: 0.00 AC: 0 AN: 29536

American (AMR) AF: 0.0000286 AC: 1 AN: 35024

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24738

East Asian (EAS) AF: 0.00 AC: 0 AN: 34188

South Asian (SAS) AF: 0.00 AC: 0 AN: 78784

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45496

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4194

European-Non Finnish (NFE) AF: 0.00000464 AC: 5 AN: 1078352

Other (OTH) AF: 0.00 AC: 0 AN: 57590

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152006 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74228

African (AFR) AF: 0.00 AC: 0 AN: 41432

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5136

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000442 AC: 3 AN: 67948

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 09, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.176C>T (p.P59L) alteration is located in exon 1 (coding exon 1) of the EDEM1 gene. This alteration results from a C to T substitution at nucleotide position 176, causing the proline (P) at amino acid position 59 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.082	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	12
DANN	Uncertain	0.99
DEOGEN2	Benign	0.039	T
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.037	N
LIST_S2	Benign	0.59	T
M_CAP	Pathogenic	0.97	D
MetaRNN	Benign	0.25	T
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.24
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.46	N
REVEL	Benign	0.20
Sift	Uncertain	0.015	D
Sift4G	Benign	0.46	T
Polyphen		0.0	B
Vest4		0.11
MutPred		0.29		Gain of sheet (P = 0.0028);
MVP		0.93
MPC		0.28
ClinPred		0.15	T
GERP RS		4.2
PromoterAI		-0.068	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Varity_R		0.094
gMVP		0.56
Mutation Taster		=96/4	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

Publications

Loading publications...

Other links and lift over

dbSNP: rs1271865128; hg19: chr3-5229666;