1-19219317-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The ENST00000477853.6(EMC1):​c.2968C>T​(p.Arg990Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000248 in 1,613,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. R990Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

EMC1
ENST00000477853.6 missense

Scores

4
6
9

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.33
Variant links:
Genes affected
EMC1 (HGNC:28957): (ER membrane protein complex subunit 1) This gene encodes a single-pass type I transmembrane protein, which is a subunit of the endoplasmic reticulum membrane protein complex (EMC). Multiple alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2012]
EMC1-AS1 (HGNC:54050): (EMC1 antisense RNA 1)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.40754044).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
EMC1NM_015047.3 linkuse as main transcriptc.2968C>T p.Arg990Trp missense_variant 23/23 ENST00000477853.6 NP_055862.1
EMC1-AS1NR_135114.1 linkuse as main transcriptn.174+8758G>A intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
EMC1ENST00000477853.6 linkuse as main transcriptc.2968C>T p.Arg990Trp missense_variant 23/231 NM_015047.3 ENSP00000420608 P4Q8N766-1
EMC1-AS1ENST00000437898.3 linkuse as main transcriptn.212+8758G>A intron_variant, non_coding_transcript_variant 2

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
152052
Hom.:
0
Cov.:
32
show subpopulations
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
GnomAD3 exomes
AF:
0.0000159
AC:
4
AN:
251424
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135894
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000578
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000109
Gnomad SAS 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:
0.0000267
AC:
39
AN:
1461842
Hom.:
0
Cov.:
31
AF XY:
0.0000248
AC XY:
18
AN XY:
727230
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000671
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000252
Gnomad4 SAS exome
AF:
0.0000348
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000198
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.00000658
AC:
1
AN:
152052
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74260
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000254
Hom.:
0
Bravo
AF:
0.0000189
ExAC
AF:
0.0000247
AC:
3
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

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

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpFeb 07, 2023This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 990 of the EMC1 protein (p.Arg990Trp). This variant is present in population databases (rs755567367, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with EMC1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1367729). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt EMC1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.90
BayesDel_addAF
Benign
-0.18
T
BayesDel_noAF
Benign
-0.27
CADD
Pathogenic
34
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.16
T;.;.
Eigen
Uncertain
0.38
Eigen_PC
Uncertain
0.44
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
0.98
D;D;D
M_CAP
Benign
0.024
T
MetaRNN
Benign
0.41
T;T;T
MetaSVM
Benign
-0.47
T
MutationAssessor
Benign
1.9
L;.;.
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Uncertain
0.73
T
PROVEAN
Uncertain
-4.0
D;D;D
REVEL
Benign
0.28
Sift
Uncertain
0.0020
D;D;D
Sift4G
Uncertain
0.0070
D;D;D
Polyphen
1.0
D;D;D
Vest4
0.53
MVP
0.50
MPC
1.0
ClinPred
0.93
D
GERP RS
5.1
Varity_R
0.47
gMVP
0.52

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.050
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

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

Other links and lift over

dbSNP: rs755567367; hg19: chr1-19545811; API