16-2228516-G-C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004424.5(E4F1):​c.302G>C​(p.Gly101Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G101D) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: E4F1 NM_004424.5 missense
• Clinical Significance: Not reported in ClinVar
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.080415815).

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>C	p.Gly101Ala	missense	Exon 2 of 14	NP_004415.4	Q66K89
	E4F1	NM_001288776.2		c.302G>C	p.Gly101Ala	missense	Exon 2 of 14	NP_001275705.2	H3BUJ7
	E4F1	NM_001288778.2		c.302G>C	p.Gly101Ala	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>C	p.Gly101Ala	missense	Exon 2 of 14	ENSP00000301727.4	Q66K89
	E4F1	ENST00000564139.5	TSL:1	c.302G>C	p.Gly101Ala	missense	Exon 2 of 14	ENSP00000457672.1	H3BUJ7
	E4F1	ENST00000565090.5	TSL:1	c.302G>C	p.Gly101Ala	missense	Exon 2 of 12	ENSP00000456760.1	H3BSL4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459982 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726234

African (AFR) AF: 0.0000299 AC: 1 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: 0.00 AC: 0 AN: 1111530

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

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	6.3
DANN	Benign	0.76
DEOGEN2	Benign	0.092	T
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.82
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.0056	T
MetaRNN	Benign	0.080	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.1	L
PhyloP100		0.97
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.026
Sift	Benign	0.14	T
Sift4G	Benign	0.97	T
Polyphen		0.86	P
Vest4		0.11
MutPred		0.29		Loss of relative solvent accessibility (P = 0.0981)
MVP		0.31
MPC		0.40
ClinPred		0.048	T
GERP RS		0.49
Varity_R		0.060
gMVP		0.35

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;