Genetic Variant E2F4:p.Ser319dup (chr16-67195890-A-ACAG) – ACMG Classification: Benign (-9 pts)

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP3BA1

The NM_001950.4(E2F4):c.956_958dupGCA(p.Ser319dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0292 in 1,607,940 control chromosomes in the GnomAD database, including 161 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.036 ( 102 hom., cov: 31)

Exomes 𝑓: 0.029 ( 59 hom. )

Consequence

E2F4
NM_001950.4 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.01

Publications

11 publications found

Variant links:

Genes affected

E2F4 (HGNC:3118): (E2F transcription factor 4) 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 binds to all three of the tumor suppressor proteins pRB, p107 and p130, but with higher affinity to the last two. It plays an important role in the suppression of proliferation-associated genes, and its gene mutation and increased expression may be associated with human cancer. [provided by RefSeq, Jul 2008]

E2F4 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_001950.4

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0552 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001950.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	E2F4	NM_001950.4	MANE Select	c.956_958dupGCA	p.Ser319dup	disruptive_inframe_insertion	Exon 7 of 10	NP_001941.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
E2F4	ENST00000379378.8	TSL:1 MANE Select	c.956_958dupGCA	p.Ser319dup	disruptive_inframe_insertion	Exon 7 of 10	ENSP00000368686.3	Q16254
E2F4	ENST00000914909.1		c.956_958dupGCA	p.Ser319dup	disruptive_inframe_insertion	Exon 7 of 10	ENSP00000584968.1
E2F4	ENST00000957228.1		c.971_973dupGCA	p.Ser324dup	disruptive_inframe_insertion	Exon 7 of 10	ENSP00000627287.1

Frequencies

GnomAD3 genomes

AF:

0.0358

AC:

5384

AN:

150332

Hom.:

102

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0382

Gnomad AMI

AF:

0.0176

Gnomad AMR

AF:

0.0582

Gnomad ASJ

AF:

0.0136

Gnomad EAS

AF:

0.0297

Gnomad SAS

AF:

0.00941

Gnomad FIN

AF:

0.0507

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0309

Gnomad OTH

AF:

0.0357

GnomAD4 exome

AF:

0.0285

AC:

41583

AN:

1457512

Hom.:

Cov.:

AF XY:

0.0278

AC XY:

20154

AN XY:

724972

show subpopulations

African (AFR)

AF:

0.0403

AC:

1324

AN:

32878

American (AMR)

AF:

0.0569

AC:

2536

AN:

44572

Ashkenazi Jewish (ASJ)

AF:

0.0133

AC:

348

AN:

26072

East Asian (EAS)

AF:

0.0252

AC:

998

AN:

39532

South Asian (SAS)

AF:

0.00649

AC:

556

AN:

85722

European-Finnish (FIN)

AF:

0.0488

AC:

2589

AN:

53034

Middle Eastern (MID)

AF:

0.0155

AC:

AN:

5730

European-Non Finnish (NFE)

AF:

0.0284

AC:

31529

AN:

1109878

Other (OTH)

AF:

0.0269

AC:

1614

AN:

60094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.434

Heterozygous variant carriers

2795

5590

8386

11181

13976

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1172

2344

3516

4688

5860

<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:

0.0358

AC:

5390

AN:

150428

Hom.:

102

Cov.:

AF XY:

0.0374

AC XY:

2747

AN XY:

73430

show subpopulations

African (AFR)

AF:

0.0382

AC:

1559

AN:

40826

American (AMR)

AF:

0.0584

AC:

883

AN:

15116

Ashkenazi Jewish (ASJ)

AF:

0.0136

AC:

AN:

3464

East Asian (EAS)

AF:

0.0300

AC:

154

AN:

5132

South Asian (SAS)

AF:

0.00901

AC:

AN:

4774

European-Finnish (FIN)

AF:

0.0507

AC:

520

AN:

10256

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0309

AC:

2088

AN:

67564

Other (OTH)

AF:

0.0354

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

235

471

706

942

1177

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

156

208

260

<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:

0.0190

Hom.:

Bravo

AF:

0.0361

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.0

Mutation Taster

=75/25

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over