chr6-20482912-G-C

Variant names:

• chr6-20482912-G-C
• rs771475477
• NM_001949.5:c.876G>C

Variant summary

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

The NM_001949.5(E2F3):​c.876G>C​(p.Glu292Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,338 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: E2F3 NM_001949.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.29
• Publications: 0 publications found

Genes affected

E2F3 (HGNC:3115): (E2F transcription factor 3) This gene encodes a member of a small family of transcription factors that function through binding of DP interaction partner proteins. The encoded protein recognizes a specific sequence motif in DNA and interacts directly with the retinoblastoma protein (pRB) to regulate the expression of genes involved in the cell cycle. Altered copy number and activity of this gene have been observed in a number of human cancers. There are pseudogenes for this gene on chromosomes 2 and 17. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2013]

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=0.20343143).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001949.5. 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
	E2F3	NM_001949.5	MANE Select	c.876G>C	p.Glu292Asp	missense	Exon 4 of 7	NP_001940.1	O00716-1
	E2F3	NM_001243076.3		c.483G>C	p.Glu161Asp	missense	Exon 4 of 7	NP_001230005.1	O00716-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	E2F3	ENST00000346618.8	TSL:1 MANE Select	c.876G>C	p.Glu292Asp	missense	Exon 4 of 7	ENSP00000262904.4	O00716-1
	E2F3	ENST00000535432.2	TSL:1	c.483G>C	p.Glu161Asp	missense	Exon 4 of 7	ENSP00000443418.1	O00716-2
	E2F3	ENST00000938961.1		c.858G>C	p.Glu286Asp	missense	Exon 4 of 7	ENSP00000609020.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461338 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726998

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39670

South Asian (SAS) AF: 0.00 AC: 0 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53380

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111614

Other (OTH) AF: 0.00 AC: 0 AN: 60368

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.034	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	23
DANN	Benign	0.90
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.19
Eigen_PC	Benign	0.027
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.56	T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	0.79	N
PhyloP100		2.3
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.25	N
REVEL	Benign	0.29
Sift	Benign	0.52	T
Sift4G	Benign	0.81	T
Polyphen		0.017	B
Vest4		0.22
MutPred		0.26		Loss of helix (P = 0.1706)
MVP		0.61
MPC		0.55
ClinPred		0.52	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.18
Mutation Taster		=77/23	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: rs771475477; hg19: chr6-20483143;