12-77027888-G-A

Variant names:

• chr12-77027888-G-A
• NM_203394.3:c.2135C>T

Variant summary

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

The NM_203394.3(E2F7):​c.2135C>T​(p.Pro712Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P712R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: E2F7 NM_203394.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.93

Genes affected

E2F7 (HGNC:23820): (E2F transcription factor 7) Enables DNA-binding transcription factor activity; cis-regulatory region sequence-specific DNA binding activity; and identical protein binding activity. Involved in several processes, including DNA damage response, signal transduction by p53 class mediator; regulation of transcription, DNA-templated; and sprouting angiogenesis. Located in nuclear speck. [provided by Alliance of Genome Resources, Apr 2022]

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=0.2524009).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
E2F7	NM_203394.3	c.2135C>T	p.Pro712Leu	missense_variant	Exon 11 of 13	ENST00000322886.12	NP_976328.2
E2F7	XM_011537966.3	c.2000C>T	p.Pro667Leu	missense_variant	Exon 10 of 12		XP_011536268.1
E2F7	XM_011537969.3	c.1832C>T	p.Pro611Leu	missense_variant	Exon 10 of 12		XP_011536271.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
E2F7	ENST00000322886.12	c.2135C>T	p.Pro712Leu	missense_variant	Exon 11 of 13	1	NM_203394.3	ENSP00000323246.7
E2F7	ENST00000416496.6	c.2135C>T	p.Pro712Leu	missense_variant	Exon 11 of 12	5		ENSP00000393639.2
E2F7	ENST00000550669.5	c.*56C>T		downstream_gene_variant		1		ENSP00000448245.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 20, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2135C>T (p.P712L) alteration is located in exon 11 (coding exon 10) of the E2F7 gene. This alteration results from a C to T substitution at nucleotide position 2135, causing the proline (P) at amino acid position 712 to be replaced by a leucine (L). 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	0.11
BayesDel_addAF	Benign	-0.062	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	T;.
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.25	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.5	M;M
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-2.5	N;D
REVEL	Benign	0.16
Sift	Uncertain	0.0070	D;D
Sift4G	Uncertain	0.022	D;D
Polyphen		0.61	P;D
Vest4		0.43
MutPred		0.34		Gain of catalytic residue at A713 (P = 0.0031);Gain of catalytic residue at A713 (P = 0.0031);
MVP		0.34
MPC		0.52
ClinPred		0.89	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.073
gMVP		0.39
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: chr12-77421668;