20-33678328-C-T

Position:

• chr20-33678328-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_005225.3(E2F1):​c.598G>A​(p.Gly200Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0254 in 1,612,394 control chromosomes in the GnomAD database, including 640 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 0.022 (77 hom., cov: 33)
  • Exomes 𝑓: 0.026 (563 hom.)
• Consequence: E2F1 NM_005225.3 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -1.89

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0025356412).
• BP6: Variant 20-33678328-C-T is Benign according to our data. Variant chr20-33678328-C-T is described in ClinVar as [Benign]. Clinvar id is 3041382.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0221 (3363/152348) while in subpopulation NFE AF= 0.0307 (2087/68026). AF 95% confidence interval is 0.0296. There are 77 homozygotes in gnomad4. There are 1683 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 3363 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
E2F1	NM_005225.3	c.598G>A	p.Gly200Ser	missense_variant	4/7	ENST00000343380.6
E2F1	XM_047439961.1	c.598G>A	p.Gly200Ser	missense_variant	4/5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
E2F1	ENST00000343380.6	c.598G>A	p.Gly200Ser	missense_variant	4/7	1	NM_005225.3	P1

Frequencies

GnomAD3 genomes AF: 0.0221 AC: 3364 AN: 152230 Hom.: 77 Cov.: 33

Gnomad AFR AF: 0.00463

Gnomad AMI AF: 0.0625

Gnomad AMR AF: 0.0209

Gnomad ASJ AF: 0.0257

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00372

Gnomad FIN AF: 0.0501

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0307

Gnomad OTH AF: 0.0291

GnomAD3 exomes AF: 0.0226 AC: 5658 AN: 249998 Hom.: 104 AF XY: 0.0228 AC XY: 3082 AN XY: 135368

Gnomad AFR exome AF: 0.00411

Gnomad AMR exome AF: 0.0159

Gnomad ASJ exome AF: 0.0238

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00474

Gnomad FIN exome AF: 0.0500

Gnomad NFE exome AF: 0.0304

Gnomad OTH exome AF: 0.0254

GnomAD4 exome AF: 0.0258 AC: 37606 AN: 1460046 Hom.: 563 Cov.: 31 AF XY: 0.0253 AC XY: 18385 AN XY: 726330

Gnomad4 AFR exome AF: 0.00392

Gnomad4 AMR exome AF: 0.0163

Gnomad4 ASJ exome AF: 0.0251

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00482

Gnomad4 FIN exome AF: 0.0521

Gnomad4 NFE exome AF: 0.0282

Gnomad4 OTH exome AF: 0.0244

GnomAD4 genome AF: 0.0221 AC: 3363 AN: 152348 Hom.: 77 Cov.: 33 AF XY: 0.0226 AC XY: 1683 AN XY: 74500

Gnomad4 AFR AF: 0.00462

Gnomad4 AMR AF: 0.0209

Gnomad4 ASJ AF: 0.0257

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00372

Gnomad4 FIN AF: 0.0501

Gnomad4 NFE AF: 0.0307

Gnomad4 OTH AF: 0.0288

Alfa AF: 0.0263 Hom.: 62

Bravo AF: 0.0195

TwinsUK AF: 0.0264 AC: 98

ALSPAC AF: 0.0262 AC: 101

ESP6500AA AF: 0.00681 AC: 30

ESP6500EA AF: 0.0261 AC: 224

ExAC AF: 0.0225 AC: 2730

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.0312

EpiControl AF: 0.0311

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

E2F1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 17, 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	0.062
BayesDel_addAF	Benign	-0.80	T
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.048
DANN	Benign	0.56
DEOGEN2	Benign	0.21	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.088	N
LIST_S2	Benign	0.61	T
MetaRNN	Benign	0.0025	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.45	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.88	N
REVEL	Benign	0.023
Sift	Benign	0.80	T
Sift4G	Benign	0.53	T
Polyphen		0.022	B
Vest4		0.027
MPC		0.59
ClinPred		0.0018	T
GERP RS		-3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.030
gMVP		0.33

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

Other links and lift over

dbSNP: rs35385772; hg19: chr20-32266134;