8-85177559-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001951.4(E2F5):c.139G>A(p.Gly47Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000365 in 1,259,586 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000086 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000030 ( 0 hom. )

Consequence

E2F5
NM_001951.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.44

Variant links:

Genes affected

E2F5 (HGNC:3119): (E2F transcription factor 5) 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 evolutionarily conserved domains that are present 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 is differentially phosphorylated and is expressed in a wide variety of human tissues. It has higher identity to E2F4 than to other family members. Both this protein and E2F4 interact with tumor suppressor proteins p130 and p107, but not with pRB. Alternative splicing results in multiple variants encoding different isoforms. [provided by RefSeq, Jul 2008]

E2F5 links:

ENSG00000254208 (HGNC:):

ENSG00000254208 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.027671844).

BS2

High AC in GnomAd4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
E2F5	NM_001951.4 link	c.139G>A	p.Gly47Ser	missense_variant	Exon 1 of 8	ENST00000416274.7	NP_001942.2	Q15329-1
E2F5	NM_001083588.2 link	c.139G>A	p.Gly47Ser	missense_variant	Exon 1 of 8		NP_001077057.1	Q15329-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
E2F5	ENST00000416274.7 link	c.139G>A	p.Gly47Ser	missense_variant	Exon 1 of 8	1	NM_001951.4	ENSP00000398124.2	Q15329-1
E2F5	ENST00000418930.6 link	c.139G>A	p.Gly47Ser	missense_variant	Exon 1 of 8	1		ENSP00000414312.2	Q15329-2
ENSG00000254208	ENST00000520129.1 link	n.431C>T		non_coding_transcript_exon_variant	Exon 2 of 2	5
E2F5	ENST00000256117.9 link	n.-54G>A		upstream_gene_variant		5		ENSP00000256117.6	C9JYE9

Frequencies

GnomAD3 genomes

AF:

0.0000861

AC:

AN:

150958

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000593

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000148

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000804

AC:

AN:

62204

AF XY:

0.0000282

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000723

Gnomad ASJ exome

AF:

0.00124

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000298

AC:

AN:

1108628

Hom.:

Cov.:

AF XY:

0.0000246

AC XY:

AN XY:

528562

show subpopulations

Gnomad4 AFR exome

AF:

0.00

AC:

AN:

23798

Gnomad4 AMR exome

AF:

0.000383

AC:

AN:

13044

Gnomad4 ASJ exome

AF:

0.00107

AC:

AN:

13998

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

28192

Gnomad4 SAS exome

AF:

0.00

AC:

AN:

23032

Gnomad4 FIN exome

AF:

0.00

AC:

AN:

26742

Gnomad4 NFE exome

AF:

0.00000965

AC:

AN:

933002

Gnomad4 Remaining exome

AF:

0.0000911

AC:

AN:

43888

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000861

AC:

AN:

150958

Hom.:

Cov.:

AF XY:

0.0000814

AC XY:

AN XY:

73716

show subpopulations

Gnomad4 AFR

AF:

0.00

AC:

AN:

Gnomad4 AMR

AF:

0.000593

AC:

0.000593198

AN:

0.000593198

Gnomad4 ASJ

AF:

0.000865

AC:

0.000865052

AN:

0.000865052

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.0000148

AC:

0.000014771

AN:

0.000014771

Gnomad4 OTH

AF:

0.00

AC:

AN:

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.000144

ExAC

AF:

0.0000554

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 29, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.139G>A (p.G47S) alteration is located in exon 1 (coding exon 1) of the E2F5 gene. This alteration results from a G to A substitution at nucleotide position 139, causing the glycine (G) at amino acid position 47 to be replaced by a serine (S). 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

0.12

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.59

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.052

.;T

Eigen

Benign

-0.84

Eigen_PC

Benign

-0.72

FATHMM_MKL

Benign

0.69

LIST_S2

Benign

0.55

T;T

M_CAP

Pathogenic

0.32

MetaRNN

Benign

0.028

T;T

MetaSVM

Benign

-0.89

MutationAssessor

Benign

0.34

N;N

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

0.50

N;N

REVEL

Benign

0.047

Sift

Benign

0.47

T;T

Sift4G

Benign

0.65

T;T

Polyphen

0.062

B;B

Vest4

0.15

MutPred

0.15

Gain of phosphorylation at G47 (P = 0.0119);Gain of phosphorylation at G47 (P = 0.0119);

MVP

0.20

MPC

1.3

ClinPred

0.074

GERP RS

1.6

Varity_R

0.056

gMVP

0.23

Mutation Taster

=80/20

polymorphism

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