16-2228516-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_004424.5(E4F1):​c.302G>A​(p.Gly101Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,982 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

E4F1
NM_004424.5 missense

Scores

2
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.970
Variant links:
Genes affected
E4F1 (HGNC:3121): (E4F transcription factor 1) The zinc finger protein encoded by this gene is one of several cellular transcription factors whose DNA-binding activities are regulated through the action of adenovirus E1A. A 50-kDa amino-terminal product is generated from the full-length protein through proteolytic cleavage. The protein is differentially regulated by E1A-induced phosphorylation. The full-length gene product represses transcription from the E4 promoter in the absence of E1A, while the 50-kDa form acts as a transcriptional activator in its presence. Alternative splicing results in multiple transcripts encoding different proteins. [provided by RefSeq, Jan 2014]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.06721258).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
E4F1NM_004424.5 linkuse as main transcriptc.302G>A p.Gly101Asp missense_variant 2/14 ENST00000301727.9 NP_004415.4

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
E4F1ENST00000301727.9 linkuse as main transcriptc.302G>A p.Gly101Asp missense_variant 2/141 NM_004424.5 ENSP00000301727.4 Q66K89

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1459982
Hom.:
0
Cov.:
32
AF XY:
0.00000138
AC XY:
1
AN XY:
726234
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:
0.00
Gnomad4 NFE exome
AF:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
Alfa
AF:
0.0000331
Hom.:
0
Bravo
AF:
0.00000378

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 GeneticsJul 11, 2022The c.302G>A (p.G101D) alteration is located in exon 2 (coding exon 2) of the E4F1 gene. This alteration results from a G to A substitution at nucleotide position 302, causing the glycine (G) at amino acid position 101 to be replaced by an aspartic acid (D). 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
0.15
BayesDel_addAF
Benign
-0.25
T
BayesDel_noAF
Benign
-0.59
CADD
Benign
7.4
DANN
Benign
0.65
DEOGEN2
Benign
0.098
T;.;.;T
Eigen
Benign
-1.0
Eigen_PC
Benign
-0.88
FATHMM_MKL
Uncertain
0.77
D
LIST_S2
Benign
0.63
T;T;T;T
M_CAP
Benign
0.0057
T
MetaRNN
Benign
0.067
T;T;T;T
MetaSVM
Benign
-0.91
T
MutationAssessor
Benign
0.69
N;.;.;.
PrimateAI
Uncertain
0.60
T
PROVEAN
Benign
-0.79
N;N;N;N
REVEL
Benign
0.021
Sift
Benign
0.22
T;T;T;T
Sift4G
Benign
0.78
T;T;T;T
Polyphen
0.018
B;.;.;.
Vest4
0.29
MutPred
0.29
Gain of solvent accessibility (P = 0.0354);Gain of solvent accessibility (P = 0.0354);Gain of solvent accessibility (P = 0.0354);.;
MVP
0.27
MPC
0.49
ClinPred
0.047
T
GERP RS
0.49
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.071
gMVP
0.39

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: rs1332142497; hg19: chr16-2278517; API