Genetic Variant E2F8:p.Arg825His (chr11-19224788-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_024680.4(E2F8):c.2474G>A(p.Arg825His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000452 in 1,613,968 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000049 ( 0 hom. )

Consequence

E2F8
NM_024680.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.91

Variant links:

Genes affected

E2F8 (HGNC:24727): (E2F transcription factor 8) This gene encodes a member of a family of transcription factors which regulate the expression of genes required for progression through the cell cycle. The encoded protein regulates progression from G1 to S phase by ensuring the nucleus divides at the proper time. Multiple alternatively spliced variants, encoding the same protein, have been identified. [provided by RefSeq, Jan 2012]

E2F8 links:

CSRP3-AS1 (HGNC:54183): (CSRP3 and E2F8 antisense RNA 1)

CSRP3-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.17817384).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
E2F8	NM_024680.4 link	c.2474G>A	p.Arg825His	missense_variant	Exon 13 of 13	ENST00000250024.9	NP_078956.2	A0AVK6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
E2F8	ENST00000250024.9 link	c.2474G>A	p.Arg825His	missense_variant	Exon 13 of 13	1	NM_024680.4	ENSP00000250024.4	A0AVK6
E2F8	ENST00000527884.5 link	c.2474G>A	p.Arg825His	missense_variant	Exon 13 of 13	2		ENSP00000434199.1	A0AVK6
E2F8	ENST00000620009.4 link	c.2474G>A	p.Arg825His	missense_variant	Exon 13 of 13	5		ENSP00000481103.1	A0AVK6
CSRP3-AS1	ENST00000527978.1 link	n.146-46C>T		intron_variant	Intron 1 of 3	5

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152076

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000557

AC:

AN:

251416

Hom.:

AF XY:

0.0000589

AC XY:

AN XY:

135880

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000106

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000486

AC:

AN:

1461892

Hom.:

Cov.:

AF XY:

0.0000440

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000562

Gnomad4 NFE exome

AF:

0.0000567

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000132

AC:

AN:

152076

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74240

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000381

Hom.:

Bravo

AF:

0.0000113

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000107

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 08, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2474G>A (p.R825H) alteration is located in exon 13 (coding exon 12) of the E2F8 gene. This alteration results from a G to A substitution at nucleotide position 2474, causing the arginine (R) at amino acid position 825 to be replaced by a histidine (H). 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

0.089

BayesDel_addAF

Benign

-0.024

BayesDel_noAF

Uncertain

-0.060

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.089

T;T;T

Eigen

Uncertain

0.35

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Uncertain

0.87

LIST_S2

Benign

0.85

.;T;.

M_CAP

Benign

0.012

MetaRNN

Benign

0.18

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.0

M;M;M

PrimateAI

Benign

0.47

PROVEAN

Benign

-0.92

N;.;N

REVEL

Benign

0.17

Sift

Benign

0.27

T;.;T

Sift4G

Benign

0.36

T;T;T

Polyphen

0.88

P;P;P

Vest4

0.33

MVP

0.53

MPC

0.19

ClinPred

0.12

GERP RS

6.1

Varity_R

0.074

gMVP

0.43

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