11-32602345-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_006360.6(EIF3M):ā€‹c.1071G>Cā€‹(p.Trp357Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000329 in 1,612,160 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.000059 ( 0 hom., cov: 32)
Exomes š‘“: 0.000030 ( 0 hom. )

Consequence

EIF3M
NM_006360.6 missense

Scores

12
5
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.90
Variant links:
Genes affected
EIF3M (HGNC:24460): (eukaryotic translation initiation factor 3 subunit M) This gene encodes a protein that is part of the eurkaryotic translation initiation factor 3 complete (eIF-3) required for protein synthesis. Elevated levels of the encoded protein are present in cancer cell lines. Inactivation of the encoded protein has been shown to interfere with translation of herpes virus mRNAs by preventing the association of mRNAs with the ribosomes. A pseudogene of this gene is located on the X chromosome. [provided by RefSeq, Dec 2011]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.952

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
EIF3MNM_006360.6 linkuse as main transcriptc.1071G>C p.Trp357Cys missense_variant 11/11 ENST00000531120.6 NP_006351.2 Q7L2H7-1
EIF3MNM_001307929.2 linkuse as main transcriptc.675G>C p.Trp225Cys missense_variant 8/8 NP_001294858.1 Q7L2H7-2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
EIF3MENST00000531120.6 linkuse as main transcriptc.1071G>C p.Trp357Cys missense_variant 11/111 NM_006360.6 ENSP00000436049.1 Q7L2H7-1
EIF3MENST00000524896.5 linkuse as main transcriptc.675G>C p.Trp225Cys missense_variant 8/82 ENSP00000436787.1 Q7L2H7-2
EIF3MENST00000526267.1 linkuse as main transcriptc.630G>C p.Trp210Cys missense_variant 8/82 ENSP00000432139.1 H0YCQ8
EIF3MENST00000525054.1 linkuse as main transcriptn.*43G>C downstream_gene_variant 2

Frequencies

GnomAD3 genomes
AF:
0.0000593
AC:
9
AN:
151816
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:
0.000133
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000159
AC:
4
AN:
251172
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135778
show subpopulations
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 SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000352
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000301
AC:
44
AN:
1460344
Hom.:
0
Cov.:
30
AF XY:
0.0000344
AC XY:
25
AN XY:
726522
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000187
Gnomad4 NFE exome
AF:
0.0000387
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000593
AC:
9
AN:
151816
Hom.:
0
Cov.:
32
AF XY:
0.0000405
AC XY:
3
AN XY:
74102
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:
0.000133
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000565
Hom.:
0
Bravo
AF:
0.0000453
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000116
AC:
1

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJun 28, 2022The c.1071G>C (p.W357C) alteration is located in exon 11 (coding exon 11) of the EIF3M gene. This alteration results from a G to C substitution at nucleotide position 1071, causing the tryptophan (W) at amino acid position 357 to be replaced by a cysteine (C). 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
Pathogenic
0.96
BayesDel_addAF
Pathogenic
0.31
D
BayesDel_noAF
Pathogenic
0.32
CADD
Pathogenic
32
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.59
D;.;T
Eigen
Pathogenic
0.95
Eigen_PC
Pathogenic
0.92
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.96
D;D;D
M_CAP
Benign
0.069
D
MetaRNN
Pathogenic
0.95
D;D;D
MetaSVM
Uncertain
0.17
D
MutationAssessor
Uncertain
2.8
M;.;.
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Pathogenic
0.88
D
PROVEAN
Pathogenic
-11
D;D;D
REVEL
Pathogenic
0.78
Sift
Pathogenic
0.0
D;D;D
Sift4G
Pathogenic
0.0
D;D;D
Polyphen
1.0
D;.;.
Vest4
0.96
MutPred
0.77
Loss of MoRF binding (P = 0.0034);.;.;
MVP
0.89
MPC
2.2
ClinPred
0.99
D
GERP RS
5.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.93
gMVP
0.88

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

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

Other links and lift over

dbSNP: rs374239887; hg19: chr11-32623891; API