20-33677440-C-T

Position:

chr20-33677440-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_005225.3(E2F1):c.826G>A(p.Val276Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00094 in 1,614,044 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.0048 ( 8 hom., cov: 32)

Exomes 𝑓: 0.00054 ( 8 hom. )

Consequence

E2F1
NM_005225.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.253

Variant links:

Genes affected

E2F1 (HGNC:3113): (E2F transcription factor 1) 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 and another 2 members, E2F2 and E2F3, have an additional cyclin binding domain. This protein binds preferentially to retinoblastoma protein pRB in a cell-cycle dependent manner. It can mediate both cell proliferation and p53-dependent/independent apoptosis. [provided by RefSeq, Jul 2008]

E2F1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0027939975).

BP6

Variant 20-33677440-C-T is Benign according to our data. Variant chr20-33677440-C-T is described in ClinVar as [Benign]. Clinvar id is 719834.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00478 (728/152284) while in subpopulation AFR AF= 0.0161 (670/41550). AF 95% confidence interval is 0.0151. There are 8 homozygotes in gnomad4. There are 344 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 728 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
E2F1	NM_005225.3 linkuse as main transcript	c.826G>A	p.Val276Met	missense_variant	5/7	ENST00000343380.6	NP_005216.1
E2F1	XM_047439961.1 linkuse as main transcript	c.*68G>A		3_prime_UTR_variant	5/5		XP_047295917.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
E2F1	ENST00000343380.6 linkuse as main transcript	c.826G>A	p.Val276Met	missense_variant	5/7	1	NM_005225.3	ENSP00000345571	P1

Frequencies

GnomAD3 genomes

AF:

0.00479

AC:

729

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0162

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00301

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00430

GnomAD3 exomes

AF:

0.00117

AC:

293

AN:

251294

Hom.:

AF XY:

0.000854

AC XY:

116

AN XY:

135808

show subpopulations

Gnomad AFR exome

AF:

0.0166

Gnomad AMR exome

AF:

0.000405

Gnomad ASJ exome

AF:

0.0000994

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.00114

GnomAD4 exome

AF:

0.000540

AC:

789

AN:

1461760

Hom.:

Cov.:

AF XY:

0.000455

AC XY:

331

AN XY:

727200

show subpopulations

Gnomad4 AFR exome

AF:

0.0193

Gnomad4 AMR exome

AF:

0.000783

Gnomad4 ASJ exome

AF:

0.0000765

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000108

Gnomad4 OTH exome

AF:

0.00146

GnomAD4 genome

AF:

0.00478

AC:

728

AN:

152284

Hom.:

Cov.:

AF XY:

0.00462

AC XY:

344

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.0161

Gnomad4 AMR

AF:

0.00301

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00426

Alfa

AF:

0.00108

Hom.:

Bravo

AF:

0.00628

ESP6500AA

AF:

0.0177

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00151

AC:

183

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 18, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

E2F1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 04, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.51

CADD

Benign

7.3

DANN

Benign

0.95

DEOGEN2

Benign

0.19

Eigen

Benign

-0.66

Eigen_PC

Benign

-0.62

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.61

MetaRNN

Benign

0.0028

MetaSVM

Benign

-0.80

MutationAssessor

Benign

1.7

MutationTaster

Benign

1.0

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.20

REVEL

Benign

0.11

Sift

Uncertain

0.022

Sift4G

Uncertain

0.049

Polyphen

0.049

Vest4

0.082

MVP

0.51

MPC

0.61

ClinPred

0.0054

GERP RS

1.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.13

gMVP

0.14

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over