6-20402544-C-G

Position:

• chr6-20402544-C-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001949.5(E2F3):​c.312C>G​(p.His104Gln) 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 benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: E2F3 NM_001949.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.883

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]

LOC124901482 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06589484).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
E2F3	NM_001949.5	c.312C>G	p.His104Gln	missense_variant	1/7	ENST00000346618.8	NP_001940.1
LOC124901482	XM_047419652.1	c.229G>C	p.Val77Leu	missense_variant	1/3		XP_047275608.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
E2F3	ENST00000346618.8	c.312C>G	p.His104Gln	missense_variant	1/7	1	NM_001949.5	ENSP00000262904

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

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

Mar 28, 2024

The c.312C>G (p.H104Q) alteration is located in exon 1 (coding exon 1) of the E2F3 gene. This alteration results from a C to G substitution at nucleotide position 312, causing the histidine (H) at amino acid position 104 to be replaced by a glutamine (Q). 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	Benign	0.17
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	20
DANN	Benign	0.91
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.53
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.42	T
M_CAP	Uncertain	0.099	D
MetaRNN	Benign	0.066	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	0.98	N
PrimateAI	Pathogenic	0.94	D
PROVEAN	Benign	-0.090	N
REVEL	Benign	0.059
Sift	Benign	0.62	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.18
MutPred		0.29		Gain of solvent accessibility (P = 0.0155);
MVP		0.22
MPC		0.66
ClinPred		0.10	T
GERP RS		3.3
Varity_R		0.074
gMVP		0.25

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: chr6-20402775;