16-67193055-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001950.4(E2F4):​c.292A>G​(p.Ile98Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Consequence

E2F4
NM_001950.4 missense

Scores

3
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.30
Variant links:
Genes affected
E2F4 (HGNC:3118): (E2F transcription factor 4) The protein encoded by this gene is a member of the E2F family of transcription factors. The E2F family plays a crucial role in the control of cell cycle and action of tumor suppressor proteins and is also a target of the transforming proteins of small DNA tumor viruses. The E2F proteins contain several evolutionally conserved domains found in most members of the family. These domains include a DNA binding domain, a dimerization domain which determines interaction with the differentiation regulated transcription factor proteins (DP), a transactivation domain enriched in acidic amino acids, and a tumor suppressor protein association domain which is embedded within the transactivation domain. This protein binds to all three of the tumor suppressor proteins pRB, p107 and p130, but with higher affinity to the last two. It plays an important role in the suppression of proliferation-associated genes, and its gene mutation and increased expression may be associated with human cancer. [provided by RefSeq, Jul 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.20644632).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
E2F4NM_001950.4 linkc.292A>G p.Ile98Val missense_variant Exon 3 of 10 ENST00000379378.8 NP_001941.2 Q16254

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
E2F4ENST00000379378.8 linkc.292A>G p.Ile98Val missense_variant Exon 3 of 10 1 NM_001950.4 ENSP00000368686.3 Q16254

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
33

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Aug 01, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.292A>G (p.I98V) alteration is located in exon 3 (coding exon 3) of the E2F4 gene. This alteration results from a A to G substitution at nucleotide position 292, causing the isoleucine (I) at amino acid position 98 to be replaced by a valine (V). 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
Benign
0.090
BayesDel_addAF
Benign
-0.031
T
BayesDel_noAF
Benign
-0.28
CADD
Uncertain
24
DANN
Benign
0.86
DEOGEN2
Benign
0.11
T
Eigen
Benign
-0.22
Eigen_PC
Benign
-0.087
FATHMM_MKL
Uncertain
0.84
D
LIST_S2
Uncertain
0.88
D
M_CAP
Benign
0.021
T
MetaRNN
Benign
0.21
T
MetaSVM
Benign
-0.61
T
MutationAssessor
Benign
1.6
L
PrimateAI
Uncertain
0.59
T
PROVEAN
Benign
-0.030
N
REVEL
Benign
0.26
Sift
Benign
0.29
T
Sift4G
Benign
0.30
T
Polyphen
0.064
B
Vest4
0.30
MutPred
0.27
Loss of catalytic residue at I98 (P = 0.1049);
MVP
0.69
MPC
1.0
ClinPred
0.70
D
GERP RS
3.3
RBP_binding_hub_radar
1.0
RBP_regulation_power_radar
2.7
Varity_R
0.20
gMVP
0.34

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.040
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: chr16-67226958; API