Genetic Variant E2F3:p.Met33Leu (chr6-20402329-A-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001949.5(E2F3):c.97A>T(p.Met33Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000000686 in 1,458,716 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M33V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

E2F3
NM_001949.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.79

Publications

0 publications found

Variant links:

Genes affected

E2F3 (HGNC:3115): (E2F transcription factor 3) This gene encodes a member of a small family of transcription factors that function through binding of DP interaction partner proteins. The encoded protein recognizes a specific sequence motif in DNA and interacts directly with the retinoblastoma protein (pRB) to regulate the expression of genes involved in the cell cycle. Altered copy number and activity of this gene have been observed in a number of human cancers. There are pseudogenes for this gene on chromosomes 2 and 17. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2013]

E2F3 links:

LOC124901482 (HGNC:):

LOC124901482 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2268143).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001949.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	E2F3	NM_001949.5	MANE Select	c.97A>T	p.Met33Leu	missense	Exon 1 of 7	NP_001940.1	O00716-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
E2F3	ENST00000346618.8	TSL:1 MANE Select	c.97A>T	p.Met33Leu	missense	Exon 1 of 7	ENSP00000262904.4	O00716-1
E2F3	ENST00000938961.1		c.97A>T	p.Met33Leu	missense	Exon 1 of 7	ENSP00000609020.1
ENSG00000289981	ENST00000748212.1		n.13T>A		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1458716

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725604

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33346

American (AMR)

AF:

0.00

AC:

AN:

44590

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26034

East Asian (EAS)

AF:

0.00

AC:

AN:

39608

South Asian (SAS)

AF:

0.00

AC:

AN:

86132

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51842

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5722

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111208

Other (OTH)

AF:

0.00

AC:

AN:

60234

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.59

CADD

Benign

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.18

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.25

FATHMM_MKL

Benign

0.49

LIST_S2

Uncertain

0.90

M_CAP

Benign

0.015

MetaRNN

Benign

0.23

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.0

PhyloP100

3.8

PrimateAI

Pathogenic

0.92

PROVEAN

Benign

-0.30

REVEL

Benign

0.098

Sift

Benign

0.47

Sift4G

Uncertain

0.047

Polyphen

0.024

Vest4

0.67

MutPred

0.24

Gain of glycosylation at S32 (P = 0.0454)

MVP

0.32

MPC

0.62

ClinPred

0.16

GERP RS

3.5

PromoterAI

-0.025

Neutral

(source)

Varity_R

0.097

gMVP

0.29

Mutation Taster

=93/7

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over