16-67195890-ACAGCAGCAGCAGCAGCAGCAGCAGCAGCAG-ACAGCAGCAGCAGCAGCAGCAGCAGCAG

Variant names:

• chr16-67195890-ACAG-A
• rs3830472
• NM_001950.4:c.956_958delGCA

Variant summary

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

The NM_001950.4(E2F4):​c.956_958delGCA​(p.Ser319del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.0226 in 1,250,328 control chromosomes in the GnomAD database, including 8 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0036 (2 hom., cov: 31)
  • Exomes 𝑓: 0.025 (6 hom.)
• Consequence: E2F4 NM_001950.4 disruptive_inframe_deletion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.77
• 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 547 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.956_958delGCA	p.Ser319del	disruptive_inframe_deletion	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.956_958delGCA	p.Ser319del	disruptive_inframe_deletion	Exon 7 of 10	ENSP00000368686.3	Q16254
	E2F4	ENST00000914909.1		c.956_958delGCA	p.Ser319del	disruptive_inframe_deletion	Exon 7 of 10	ENSP00000584968.1
	E2F4	ENST00000957228.1		c.971_973delGCA	p.Ser324del	disruptive_inframe_deletion	Exon 7 of 10	ENSP00000627287.1

Frequencies

GnomAD3 genomes AF: 0.00364 AC: 546 AN: 149944 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.00359

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00432

Gnomad ASJ AF: 0.00145

Gnomad EAS AF: 0.00253

Gnomad SAS AF: 0.00376

Gnomad FIN AF: 0.00189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00406

Gnomad OTH AF: 0.00290

GnomAD4 exome AF: 0.0252 AC: 27764 AN: 1100290 Hom.: 6 AF XY: 0.0276 AC XY: 14611 AN XY: 529010

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0243 AC: 586 AN: 24108

American (AMR) AF: 0.0591 AC: 1597 AN: 27008

Ashkenazi Jewish (ASJ) AF: 0.0414 AC: 646 AN: 15606

East Asian (EAS) AF: 0.0686 AC: 1340 AN: 19544

South Asian (SAS) AF: 0.0593 AC: 2162 AN: 36432

European-Finnish (FIN) AF: 0.0502 AC: 1636 AN: 32604

Middle Eastern (MID) AF: 0.0335 AC: 140 AN: 4180

European-Non Finnish (NFE) AF: 0.0205 AC: 18409 AN: 899514

Other (OTH) AF: 0.0302 AC: 1248 AN: 41294

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00365 AC: 547 AN: 150038 Hom.: 2 Cov.: 31 AF XY: 0.00377 AC XY: 276 AN XY: 73228

African (AFR) AF: 0.00363 AC: 148 AN: 40786

American (AMR) AF: 0.00431 AC: 65 AN: 15072

Ashkenazi Jewish (ASJ) AF: 0.00145 AC: 5 AN: 3460

East Asian (EAS) AF: 0.00254 AC: 13 AN: 5126

South Asian (SAS) AF: 0.00377 AC: 18 AN: 4772

European-Finnish (FIN) AF: 0.00189 AC: 19 AN: 10076

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00405 AC: 273 AN: 67454

Other (OTH) AF: 0.00287 AC: 6 AN: 2090

Alfa AF: 0.0950 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.8
Mutation Taster		=80/20	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs3830472; hg19: chr16-67229793; COSMIC: COSV62605690; COSMIC: COSV62605690;