1-184711807-G-C

Position:

• chr1-184711807-G-C

Variant summary

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

The NM_025191.4(EDEM3):​c.1607C>G​(p.Pro536Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: EDEM3 NM_025191.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.88

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]

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	Protein	UniProt
EDEM3	NM_025191.4	c.1607C>G	p.Pro536Arg	missense_variant	15/20	ENST00000318130.13	NP_079467.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EDEM3	ENST00000318130.13	c.1607C>G	p.Pro536Arg	missense_variant	15/20	1	NM_025191.4	ENSP00000318147	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 08, 2023

The c.1607C>G (p.P536R) alteration is located in exon 15 (coding exon 15) of the EDEM3 gene. This alteration results from a C to G substitution at nucleotide position 1607, causing the proline (P) at amino acid position 536 to be replaced by an arginine (R). 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	Uncertain	0.50
BayesDel_addAF	Uncertain	0.045	T
BayesDel_noAF	Benign	-0.17
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.20	T;.
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.86	D;D
M_CAP	Benign	0.025	D
MetaRNN	Uncertain	0.50	T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	2.0	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Pathogenic	-4.5	D;D
REVEL	Uncertain	0.31
Sift	Benign	0.093	T;T
Sift4G	Benign	0.16	T;T
Polyphen		0.026	B;.
Vest4		0.63
MVP		0.78
MPC		0.17
ClinPred		0.77	D
GERP RS		5.9
Varity_R		0.17
gMVP		0.85

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

LitVar

Other links and lift over

dbSNP: rs1650252385; hg19: chr1-184680941;