20-33676869-C-T

Position:

chr20-33676869-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_005225.3(E2F1):c.1177G>A(p.Gly393Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0282 in 1,582,400 control chromosomes in the GnomAD database, including 761 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.018 ( 36 hom., cov: 32)

Exomes 𝑓: 0.029 ( 725 hom. )

Consequence

E2F1
NM_005225.3 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: -2.31

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0020274818).

BP6

Variant 20-33676869-C-T is Benign according to our data. Variant chr20-33676869-C-T is described in ClinVar as [Benign]. Clinvar id is 3041546.Status of the report is no_assertion_criteria_provided, 0 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.018 (2738/152272) while in subpopulation NFE AF= 0.0296 (2014/67994). AF 95% confidence interval is 0.0285. There are 36 homozygotes in gnomad4. There are 1220 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 2738 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
E2F1	NM_005225.3 linkuse as main transcript	c.1177G>A	p.Gly393Ser	missense_variant	7/7	ENST00000343380.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
E2F1	ENST00000343380.6 linkuse as main transcript	c.1177G>A	p.Gly393Ser	missense_variant	7/7	1	NM_005225.3	P1

Frequencies

GnomAD3 genomes

AF:

0.0180

AC:

2739

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00492

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0130

Gnomad ASJ

AF:

0.0323

Gnomad EAS

AF:

0.000963

Gnomad SAS

AF:

0.0139

Gnomad FIN

AF:

0.00913

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0297

Gnomad OTH

AF:

0.0153

GnomAD3 exomes

AF:

0.0193

AC:

3798

AN:

196584

Hom.:

AF XY:

0.0200

AC XY:

2124

AN XY:

106294

show subpopulations

Gnomad AFR exome

AF:

0.00449

Gnomad AMR exome

AF:

0.0114

Gnomad ASJ exome

AF:

0.0308

Gnomad EAS exome

AF:

0.000205

Gnomad SAS exome

AF:

0.0174

Gnomad FIN exome

AF:

0.00990

Gnomad NFE exome

AF:

0.0285

Gnomad OTH exome

AF:

0.0250

GnomAD4 exome

AF:

0.0292

AC:

41823

AN:

1430128

Hom.:

725

Cov.:

AF XY:

0.0289

AC XY:

20463

AN XY:

708802

show subpopulations

Gnomad4 AFR exome

AF:

0.00452

Gnomad4 AMR exome

AF:

0.0126

Gnomad4 ASJ exome

AF:

0.0316

Gnomad4 EAS exome

AF:

0.000159

Gnomad4 SAS exome

AF:

0.0180

Gnomad4 FIN exome

AF:

0.0104

Gnomad4 NFE exome

AF:

0.0335

Gnomad4 OTH exome

AF:

0.0264

GnomAD4 genome

AF:

0.0180

AC:

2738

AN:

152272

Hom.:

Cov.:

AF XY:

0.0164

AC XY:

1220

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.00491

Gnomad4 AMR

AF:

0.0130

Gnomad4 ASJ

AF:

0.0323

Gnomad4 EAS

AF:

0.000966

Gnomad4 SAS

AF:

0.0141

Gnomad4 FIN

AF:

0.00913

Gnomad4 NFE

AF:

0.0296

Gnomad4 OTH

AF:

0.0151

Alfa

AF:

0.0253

Hom.:

Bravo

AF:

0.0190

TwinsUK

AF:

0.0334

AC:

124

ALSPAC

AF:

0.0330

AC:

127

ESP6500AA

AF:

0.00569

AC:

ESP6500EA

AF:

0.0309

AC:

265

ExAC

AF:

0.0156

AC:

1876

Asia WGS

AF:

0.00953

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

E2F1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 09, 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

0.067

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.78

CADD

Benign

0.44

DANN

Benign

0.85

DEOGEN2

Benign

0.19

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.098

LIST_S2

Benign

0.65

MetaRNN

Benign

0.0020

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.23

MutationTaster

Benign

0.99

PrimateAI

Benign

0.30

PROVEAN

Benign

0.49

REVEL

Benign

0.053

Sift

Benign

0.70

Sift4G

Benign

1.0

Polyphen

0.022

Vest4

0.058

MPC

0.60

ClinPred

0.0032

GERP RS

-2.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.030

gMVP

0.22

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