6-20486716-T-G

Position:

• chr6-20486716-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001949.5(E2F3):​c.912T>G​(p.Ile304Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: E2F3 NM_001949.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.94

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.834

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
E2F3	NM_001949.5	c.912T>G	p.Ile304Met	missense_variant	5/7	ENST00000346618.8	NP_001940.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
E2F3	ENST00000346618.8	c.912T>G	p.Ile304Met	missense_variant	5/7	1	NM_001949.5	ENSP00000262904
E2F3	ENST00000535432.2	c.519T>G	p.Ile173Met	missense_variant	5/7	1		ENSP00000443418	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 03, 2021

The c.912T>G (p.I304M) alteration is located in exon 5 (coding exon 5) of the E2F3 gene. This alteration results from a T to G substitution at nucleotide position 912, causing the isoleucine (I) at amino acid position 304 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.42	T;.
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.83	D;D
MetaSVM	Uncertain	0.70	D
MutationAssessor	Uncertain	2.6	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.9	N;N
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.014	D;D
Polyphen		0.94	P;.
Vest4		0.90
MutPred		0.47		Gain of sheet (P = 0.0827);.;
MVP		0.96
MPC		0.82
ClinPred		0.94	D
GERP RS		4.8
Varity_R		0.46
gMVP		0.55

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-20486947;