NM_004424.5:c.156A>G

Variant names:

• chr16-2223769-A-G
• rs2093413276
• NM_004424.5:c.156A>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_004424.5(E4F1):​c.156A>G​(p.Glu52Glu) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000145 in 1,384,042 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: E4F1 NM_004424.5 splice_region, synonymous
• Scores: Splicing: ADA: 0.9978
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.95
• Publications: 0 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004424.5. 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
	E4F1	NM_004424.5	MANE Select	c.156A>G	p.Glu52Glu	splice_region synonymous	Exon 1 of 14	NP_004415.4	Q66K89
	E4F1	NM_001288776.2		c.156A>G	p.Glu52Glu	splice_region synonymous	Exon 1 of 14	NP_001275705.2	H3BUJ7
	E4F1	NM_001288778.2		c.156A>G	p.Glu52Glu	splice_region synonymous	Exon 1 of 12	NP_001275707.2	H3BSL4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	E4F1	ENST00000301727.9	TSL:1 MANE Select	c.156A>G	p.Glu52Glu	splice_region synonymous	Exon 1 of 14	ENSP00000301727.4	Q66K89
	E4F1	ENST00000564139.5	TSL:1	c.156A>G	p.Glu52Glu	splice_region synonymous	Exon 1 of 14	ENSP00000457672.1	H3BUJ7
	E4F1	ENST00000565090.5	TSL:1	c.156A>G	p.Glu52Glu	splice_region synonymous	Exon 1 of 12	ENSP00000456760.1	H3BSL4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000145 AC: 2 AN: 1384042 Hom.: 0 Cov.: 31 AF XY: 0.00000146 AC XY: 1 AN XY: 685296

African (AFR) AF: 0.00 AC: 0 AN: 29026

American (AMR) AF: 0.00 AC: 0 AN: 34634

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23520

East Asian (EAS) AF: 0.00 AC: 0 AN: 35410

South Asian (SAS) AF: 0.00 AC: 0 AN: 78970

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35544

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5466

European-Non Finnish (NFE) AF: 0.00000185 AC: 2 AN: 1083964

Other (OTH) AF: 0.00 AC: 0 AN: 57508

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	21
DANN	Benign	0.74
PhyloP100		1.9
PromoterAI		-0.31	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.78
SpliceAI score (max)		0.44		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.44		Position offset: 1

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

Other links and lift over

dbSNP: rs2093413276; hg19: chr16-2273770;