16-67195890-ACAGCAGCAGCAGCAGCAGCAGCAGCAGCAG-ACAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAG

Variant names:

• chr16-67195890-A-ACAGCAGCAGCAGCAG
• rs3830472
• NM_001950.4:c.944_958dupGCAGCAGCAGCAGCA

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP3 BS2

The NM_001950.4(E2F4):​c.944_958dupGCAGCAGCAGCAGCA​(p.Ser315_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 0.00342 in 150,442 control chromosomes in the GnomAD database, including 2 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0034 (2 hom., cov: 31)
  • Exomes 𝑓: 0.0025 (4 hom.)
  • Failed GnomAD Quality Control
• 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: Likely_benign. The variant received -5 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001950.4
• BS2: High AC in GnomAd4 at 515 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.944_958dupGCAGCAGCAGCAGCA	p.Ser315_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.944_958dupGCAGCAGCAGCAGCA	p.Ser315_Ser319dup	disruptive_inframe_insertion	Exon 7 of 10	ENSP00000368686.3	Q16254
	E2F4	ENST00000914909.1		c.944_958dupGCAGCAGCAGCAGCA	p.Ser315_Ser319dup	disruptive_inframe_insertion	Exon 7 of 10	ENSP00000584968.1
	E2F4	ENST00000957228.1		c.959_973dupGCAGCAGCAGCAGCA	p.Ser320_Ser324dup	disruptive_inframe_insertion	Exon 7 of 10	ENSP00000627287.1

Frequencies

GnomAD3 genomes AF: 0.00343 AC: 515 AN: 150346 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.00621

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00437

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000389

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00312

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00216

Gnomad OTH AF: 0.00773

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00248 AC: 3613 AN: 1457438 Hom.: 4 Cov.: 30 AF XY: 0.00241 AC XY: 1745 AN XY: 724966

African (AFR) AF: 0.00684 AC: 225 AN: 32888

American (AMR) AF: 0.00224 AC: 100 AN: 44568

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26076

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39534

South Asian (SAS) AF: 0.000385 AC: 33 AN: 85728

European-Finnish (FIN) AF: 0.00219 AC: 116 AN: 53052

Middle Eastern (MID) AF: 0.00227 AC: 13 AN: 5730

European-Non Finnish (NFE) AF: 0.00268 AC: 2979 AN: 1109762

Other (OTH) AF: 0.00236 AC: 142 AN: 60100

GnomAD4 genome AF: 0.00342 AC: 515 AN: 150442 Hom.: 2 Cov.: 31 AF XY: 0.00308 AC XY: 226 AN XY: 73438

African (AFR) AF: 0.00620 AC: 253 AN: 40828

American (AMR) AF: 0.00437 AC: 66 AN: 15116

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

East Asian (EAS) AF: 0.000390 AC: 2 AN: 5132

South Asian (SAS) AF: 0.00 AC: 0 AN: 4774

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00216 AC: 146 AN: 67572

Other (OTH) AF: 0.00765 AC: 16 AN: 2092

Alfa AF: 0.00 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;