6-20490197-G-T

Variant names:

• chr6-20490197-G-T
• rs4134982
• NM_001949.5:c.1165G>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001949.5(E2F3):​c.1165G>T​(p.Asp389Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,050 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. D389N) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: E2F3 NM_001949.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.71

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21704239).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
E2F3	NM_001949.5	c.1165G>T	p.Asp389Tyr	missense_variant	Exon 7 of 7	ENST00000346618.8	NP_001940.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
E2F3	ENST00000346618.8	c.1165G>T	p.Asp389Tyr	missense_variant	Exon 7 of 7	1	NM_001949.5	ENSP00000262904.4
E2F3	ENST00000535432.2	c.772G>T	p.Asp258Tyr	missense_variant	Exon 7 of 7	1		ENSP00000443418.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250498 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135382

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461050 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726780

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.38	T;.
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.86	D;D
M_CAP	Benign	0.0073	T
MetaRNN	Benign	0.22	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	2.0	M;.
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-1.8	N;N
REVEL	Benign	0.090
Sift	Uncertain	0.0080	D;D
Sift4G	Uncertain	0.029	D;D
Polyphen		0.95	P;.
Vest4		0.42
MutPred		0.23		Gain of phosphorylation at D389 (P = 0.0233);.;
MVP		0.37
MPC		0.70
ClinPred		0.77	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.43

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs4134982; hg19: chr6-20490428;