3-186785009-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_001967.4(EIF4A2):​c.256A>C​(p.Thr86Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Consequence

EIF4A2
NM_001967.4 missense

Scores

8
7
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.74
Variant links:
Genes affected
EIF4A2 (HGNC:3284): (eukaryotic translation initiation factor 4A2) Enables ATP hydrolysis activity. Involved in negative regulation of RNA-directed 5'-3' RNA polymerase activity. Located in perinuclear region of cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]
SNORD2 (HGNC:32678): (small nucleolar RNA, C/D box 2)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.904

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
EIF4A2NM_001967.4 linkc.256A>C p.Thr86Pro missense_variant Exon 4 of 11 ENST00000323963.10 NP_001958.2 Q14240-1
SNORD2NR_002587.1 linkn.*144A>C downstream_gene_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
EIF4A2ENST00000323963.10 linkc.256A>C p.Thr86Pro missense_variant Exon 4 of 11 1 NM_001967.4 ENSP00000326381.5 Q14240-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
33

ClinVar

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

Submissions by phenotype

not provided Uncertain:1
Nov 17, 2023
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.25
D
BayesDel_noAF
Uncertain
0.12
CADD
Pathogenic
34
DANN
Uncertain
1.0
DEOGEN2
Benign
0.15
T;T;.;.
Eigen
Pathogenic
0.86
Eigen_PC
Pathogenic
0.78
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.89
D;T;T;T
M_CAP
Benign
0.027
D
MetaRNN
Pathogenic
0.90
D;D;D;D
MetaSVM
Benign
-0.78
T
MutationAssessor
Uncertain
2.8
.;M;.;.
PrimateAI
Pathogenic
0.83
D
PROVEAN
Pathogenic
-5.4
D;D;D;.
REVEL
Uncertain
0.64
Sift
Uncertain
0.0010
D;D;D;.
Sift4G
Pathogenic
0.0010
D;D;D;D
Polyphen
1.0, 1.0
.;D;D;.
Vest4
0.77, 0.78
MutPred
0.79
Gain of ubiquitination at K83 (P = 0.0797);Gain of ubiquitination at K83 (P = 0.0797);.;.;
MVP
0.87
MPC
3.2
ClinPred
1.0
D
GERP RS
4.7
Varity_R
0.95
gMVP
0.98

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-186502798; API