16-2235356-C-T

Variant names:

• chr16-2235356-C-T
• rs26840
• NM_004424.5:c.2139C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_004424.5(E4F1):​c.2139C>T​(p.Ile713Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.401 in 1,609,234 control chromosomes in the GnomAD database, including 134,148 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.33 (9773 hom., cov: 33)
  • Exomes 𝑓: 0.41 (124375 hom.)
• Consequence: E4F1 NM_004424.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.41
• Publications: 26 publications found

Genes affected

E4F1 (HGNC:3121): (E4F transcription factor 1) The zinc finger protein encoded by this gene is one of several cellular transcription factors whose DNA-binding activities are regulated through the action of adenovirus E1A. A 50-kDa amino-terminal product is generated from the full-length protein through proteolytic cleavage. The protein is differentially regulated by E1A-induced phosphorylation. The full-length gene product represses transcription from the E4 promoter in the absence of E1A, while the 50-kDa form acts as a transcriptional activator in its presence. Alternative splicing results in multiple transcripts encoding different proteins. [provided by RefSeq, Jan 2014]

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP7: Synonymous conserved (PhyloP=-1.41 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.422 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
E4F1	NM_004424.5	c.2139C>T	p.Ile713Ile	synonymous_variant	Exon 14 of 14	ENST00000301727.9	NP_004415.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
E4F1	ENST00000301727.9	c.2139C>T	p.Ile713Ile	synonymous_variant	Exon 14 of 14	1	NM_004424.5	ENSP00000301727.4

Frequencies

GnomAD3 genomes AF: 0.328 AC: 49809 AN: 151970 Hom.: 9776 Cov.: 33

Gnomad AFR AF: 0.112

Gnomad AMI AF: 0.304

Gnomad AMR AF: 0.318

Gnomad ASJ AF: 0.345

Gnomad EAS AF: 0.412

Gnomad SAS AF: 0.435

Gnomad FIN AF: 0.461

Gnomad MID AF: 0.288

Gnomad NFE AF: 0.426

Gnomad OTH AF: 0.330

GnomAD2 exomes AF: 0.386 AC: 93715 AN: 242842 AF XY: 0.396

Gnomad AFR exome AF: 0.107

Gnomad AMR exome AF: 0.289

Gnomad ASJ exome AF: 0.342

Gnomad EAS exome AF: 0.406

Gnomad FIN exome AF: 0.463

Gnomad NFE exome AF: 0.426

Gnomad OTH exome AF: 0.402

GnomAD4 exome AF: 0.408 AC: 595068 AN: 1457146 Hom.: 124375 Cov.: 79 AF XY: 0.411 AC XY: 298254 AN XY: 725006

African (AFR) AF: 0.104 AC: 3498 AN: 33476

American (AMR) AF: 0.294 AC: 13125 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.346 AC: 9039 AN: 26114

East Asian (EAS) AF: 0.419 AC: 16640 AN: 39692

South Asian (SAS) AF: 0.440 AC: 37936 AN: 86252

European-Finnish (FIN) AF: 0.462 AC: 22619 AN: 48940

Middle Eastern (MID) AF: 0.339 AC: 1954 AN: 5768

European-Non Finnish (NFE) AF: 0.420 AC: 466750 AN: 1111872

Other (OTH) AF: 0.390 AC: 23507 AN: 60344

GnomAD4 genome AF: 0.328 AC: 49819 AN: 152088 Hom.: 9773 Cov.: 33 AF XY: 0.331 AC XY: 24612 AN XY: 74348

African (AFR) AF: 0.112 AC: 4673 AN: 41540

American (AMR) AF: 0.317 AC: 4851 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.345 AC: 1197 AN: 3470

East Asian (EAS) AF: 0.413 AC: 2125 AN: 5140

South Asian (SAS) AF: 0.436 AC: 2097 AN: 4812

European-Finnish (FIN) AF: 0.461 AC: 4884 AN: 10592

Middle Eastern (MID) AF: 0.289 AC: 85 AN: 294

European-Non Finnish (NFE) AF: 0.426 AC: 28934 AN: 67928

Other (OTH) AF: 0.330 AC: 698 AN: 2112

Alfa AF: 0.372 Hom.: 14352

Bravo AF: 0.303

Asia WGS AF: 0.404 AC: 1399 AN: 3478

EpiCase AF: 0.401

EpiControl AF: 0.399

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	2.0
DANN	Benign	0.83
PhyloP100		-1.4
PromoterAI		-0.0021	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs26840; hg19: chr16-2285357; COSMIC: COSV57037722; COSMIC: COSV57037722;