16-67195890-ACAGCAGCAGCAGCAGCAGCAGCAGCAGCAG-ACAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG

Variant names:

• chr16-67195890-A-ACAGCAG
• rs3830472
• NM_001950.4:c.953_958dupGCAGCA

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP3 BS1 BS2

The NM_001950.4(E2F4):​c.953_958dupGCAGCA​(p.Ser318_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 0.00184 in 1,607,942 control chromosomes in the GnomAD database, including 9 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0057 (8 hom., cov: 31)
  • Exomes 𝑓: 0.0014 (1 hom.)
• Consequence: E2F4 NM_001950.4 disruptive_inframe_insertion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.01
• Publications: 11 publications found

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]

ACMG classification

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

• BP3: Nonframeshift variant in repetitive region in NM_001950.4
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00574 (863/150442) while in subpopulation AFR AF = 0.0167 (681/40828). AF 95% confidence interval is 0.0156. There are 8 homozygotes in GnomAd4. There are 405 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 863 AD gene.

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.953_958dupGCAGCA	p.Ser318_Ser319dup	disruptive_inframe_insertion	Exon 7 of 10	NP_001941.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	E2F4	ENST00000379378.8	TSL:1 MANE Select	c.953_958dupGCAGCA	p.Ser318_Ser319dup	disruptive_inframe_insertion	Exon 7 of 10	ENSP00000368686.3	Q16254
	E2F4	ENST00000914909.1		c.953_958dupGCAGCA	p.Ser318_Ser319dup	disruptive_inframe_insertion	Exon 7 of 10	ENSP00000584968.1
	E2F4	ENST00000957228.1		c.968_973dupGCAGCA	p.Ser323_Ser324dup	disruptive_inframe_insertion	Exon 7 of 10	ENSP00000627287.1

Frequencies

GnomAD3 genomes AF: 0.00574 AC: 863 AN: 150348 Hom.: 8 Cov.: 31

Gnomad AFR AF: 0.0167

Gnomad AMI AF: 0.00330

Gnomad AMR AF: 0.00159

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00447

Gnomad SAS AF: 0.00188

Gnomad FIN AF: 0.00312

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00111

Gnomad OTH AF: 0.00676

GnomAD4 exome AF: 0.00144 AC: 2102 AN: 1457500 Hom.: 1 Cov.: 30 AF XY: 0.00140 AC XY: 1018 AN XY: 724990

African (AFR) AF: 0.0156 AC: 513 AN: 32780

American (AMR) AF: 0.00168 AC: 75 AN: 44574

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26076

East Asian (EAS) AF: 0.00491 AC: 194 AN: 39528

South Asian (SAS) AF: 0.00140 AC: 120 AN: 85728

European-Finnish (FIN) AF: 0.00409 AC: 217 AN: 53052

Middle Eastern (MID) AF: 0.00209 AC: 12 AN: 5730

European-Non Finnish (NFE) AF: 0.000747 AC: 829 AN: 1109928

Other (OTH) AF: 0.00235 AC: 141 AN: 60104

GnomAD4 genome AF: 0.00574 AC: 863 AN: 150442 Hom.: 8 Cov.: 31 AF XY: 0.00551 AC XY: 405 AN XY: 73438

African (AFR) AF: 0.0167 AC: 681 AN: 40828

American (AMR) AF: 0.00159 AC: 24 AN: 15118

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00448 AC: 23 AN: 5132

South Asian (SAS) AF: 0.00189 AC: 9 AN: 4774

European-Finnish (FIN) AF: 0.00312 AC: 32 AN: 10260

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00111 AC: 75 AN: 67570

Other (OTH) AF: 0.00669 AC: 14 AN: 2092

Alfa AF: 0.000590 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.0
Mutation Taster		=75/25	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs3830472; hg19: chr16-67229793;