chr1-184702964-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP6_ModerateBS1BS2

The NM_025191.4(EDEM3):​c.2236C>T​(p.Pro746Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.016 in 1,611,476 control chromosomes in the GnomAD database, including 255 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.012 ( 21 hom., cov: 32)
Exomes 𝑓: 0.016 ( 234 hom. )

Consequence

EDEM3
NM_025191.4 missense

Scores

2
6
10

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 7.96
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP6
Variant 1-184702964-G-A is Benign according to our data. Variant chr1-184702964-G-A is described in ClinVar as [Benign]. Clinvar id is 3068615.Status of the report is criteria_provided_single_submitter, 1 stars.
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0115 (1756/152102) while in subpopulation NFE AF= 0.0179 (1217/67986). AF 95% confidence interval is 0.0171. There are 21 homozygotes in gnomad4. There are 858 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 21 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
EDEM3NM_025191.4 linkc.2236C>T p.Pro746Ser missense_variant Exon 19 of 20 ENST00000318130.13 NP_079467.3 Q9BZQ6-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
EDEM3ENST00000318130.13 linkc.2236C>T p.Pro746Ser missense_variant Exon 19 of 20 1 NM_025191.4 ENSP00000318147.7 Q9BZQ6-1

Frequencies

GnomAD3 genomes
AF:
0.0116
AC:
1757
AN:
151984
Hom.:
21
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00249
Gnomad AMI
AF:
0.00329
Gnomad AMR
AF:
0.00806
Gnomad ASJ
AF:
0.0256
Gnomad EAS
AF:
0.000385
Gnomad SAS
AF:
0.00436
Gnomad FIN
AF:
0.0161
Gnomad MID
AF:
0.00949
Gnomad NFE
AF:
0.0179
Gnomad OTH
AF:
0.0125
GnomAD3 exomes
AF:
0.0118
AC:
2927
AN:
248222
Hom.:
26
AF XY:
0.0118
AC XY:
1582
AN XY:
134242
show subpopulations
Gnomad AFR exome
AF:
0.00293
Gnomad AMR exome
AF:
0.00422
Gnomad ASJ exome
AF:
0.0192
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00672
Gnomad FIN exome
AF:
0.0175
Gnomad NFE exome
AF:
0.0168
Gnomad OTH exome
AF:
0.0122
GnomAD4 exome
AF:
0.0165
AC:
24077
AN:
1459374
Hom.:
234
Cov.:
31
AF XY:
0.0162
AC XY:
11755
AN XY:
726044
show subpopulations
Gnomad4 AFR exome
AF:
0.00268
Gnomad4 AMR exome
AF:
0.00450
Gnomad4 ASJ exome
AF:
0.0203
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00673
Gnomad4 FIN exome
AF:
0.0166
Gnomad4 NFE exome
AF:
0.0189
Gnomad4 OTH exome
AF:
0.0134
GnomAD4 genome
AF:
0.0115
AC:
1756
AN:
152102
Hom.:
21
Cov.:
32
AF XY:
0.0115
AC XY:
858
AN XY:
74348
show subpopulations
Gnomad4 AFR
AF:
0.00248
Gnomad4 AMR
AF:
0.00805
Gnomad4 ASJ
AF:
0.0256
Gnomad4 EAS
AF:
0.000386
Gnomad4 SAS
AF:
0.00437
Gnomad4 FIN
AF:
0.0161
Gnomad4 NFE
AF:
0.0179
Gnomad4 OTH
AF:
0.0123
Alfa
AF:
0.0167
Hom.:
44
Bravo
AF:
0.0102
TwinsUK
AF:
0.0183
AC:
68
ALSPAC
AF:
0.0202
AC:
78
ESP6500AA
AF:
0.00272
AC:
12
ESP6500EA
AF:
0.0165
AC:
142
ExAC
AF:
0.0116
AC:
1404
Asia WGS
AF:
0.00202
AC:
7
AN:
3478
EpiCase
AF:
0.0130
EpiControl
AF:
0.0146

ClinVar

Significance: Benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Congenital disorder of glycosylation, type 2v Benign:1
May 04, 2023
Molecular Genetics, Royal Melbourne Hospital
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

European Non-Finnish population allele frequency is 1.620% (rs78444298, 2196/127710 alleles, 30 homozygotes in gnomAD v2.1). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.5.1, this variant is classified as BENIGN. Following criteria are met: BA1 -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.85
BayesDel_addAF
Benign
-0.45
T
BayesDel_noAF
Benign
-0.40
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.12
T;.
Eigen
Uncertain
0.50
Eigen_PC
Uncertain
0.57
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.97
D;D
MetaRNN
Benign
0.0096
T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.6
L;.
PrimateAI
Uncertain
0.76
T
PROVEAN
Uncertain
-3.8
D;D
REVEL
Benign
0.24
Sift
Benign
0.18
T;T
Sift4G
Benign
0.24
T;T
Polyphen
0.75
P;.
Vest4
0.43
MPC
0.41
ClinPred
0.020
T
GERP RS
5.2
Varity_R
0.28
gMVP
0.76

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.26
Details are displayed if max score is > 0.2
DS_AL_spliceai
0.26
Position offset: 32

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs78444298; hg19: chr1-184672098; API