16-2228516-G-A

Variant names:

• chr16-2228516-G-A
• rs1332142497
• NM_004424.5:c.302G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004424.5(E4F1):​c.302G>A​(p.Gly101Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,982 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: E4F1 NM_004424.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.970
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06721258).

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.302G>A	p.Gly101Asp	missense	Exon 2 of 14	NP_004415.4	Q66K89
	E4F1	NM_001288776.2		c.302G>A	p.Gly101Asp	missense	Exon 2 of 14	NP_001275705.2	H3BUJ7
	E4F1	NM_001288778.2		c.302G>A	p.Gly101Asp	missense	Exon 2 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.302G>A	p.Gly101Asp	missense	Exon 2 of 14	ENSP00000301727.4	Q66K89
	E4F1	ENST00000564139.5	TSL:1	c.302G>A	p.Gly101Asp	missense	Exon 2 of 14	ENSP00000457672.1	H3BUJ7
	E4F1	ENST00000565090.5	TSL:1	c.302G>A	p.Gly101Asp	missense	Exon 2 of 12	ENSP00000456760.1	H3BSL4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459982 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726234

African (AFR) AF: 0.00 AC: 0 AN: 33462

American (AMR) AF: 0.00 AC: 0 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26096

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.00 AC: 0 AN: 86212

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52310

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5690

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111530

Other (OTH) AF: 0.00 AC: 0 AN: 60310

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000331 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	7.4
DANN	Benign	0.65
DEOGEN2	Benign	0.098	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.88
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.0057	T
MetaRNN	Benign	0.067	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.97
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.79	N
REVEL	Benign	0.021
Sift	Benign	0.22	T
Sift4G	Benign	0.78	T
Polyphen		0.018	B
Vest4		0.29
MutPred		0.29		Gain of solvent accessibility (P = 0.0354)
MVP		0.27
MPC		0.49
ClinPred		0.047	T
GERP RS		0.49
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.071
gMVP		0.39
Mutation Taster		=81/19	polymorphism

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: rs1332142497; hg19: chr16-2278517;