12-77028089-C-G

Position:

• chr12-77028089-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_203394.3(E2F7):​c.1934G>C​(p.Arg645Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00162 in 1,614,140 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0060 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (9 hom.)
• Consequence: E2F7 NM_203394.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.216

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

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003543377).
• BP6: Variant 12-77028089-C-G is Benign according to our data. Variant chr12-77028089-C-G is described in ClinVar as [Benign]. Clinvar id is 784305.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00605 (921/152260) while in subpopulation AFR AF= 0.0194 (805/41540). AF 95% confidence interval is 0.0183. There are 4 homozygotes in gnomad4. There are 453 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
E2F7	NM_203394.3	c.1934G>C	p.Arg645Thr	missense_variant	11/13	ENST00000322886.12
E2F7	XM_011537966.3	c.1799G>C	p.Arg600Thr	missense_variant	10/12
E2F7	XM_011537969.3	c.1631G>C	p.Arg544Thr	missense_variant	10/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
E2F7	ENST00000322886.12	c.1934G>C	p.Arg645Thr	missense_variant	11/13	1	NM_203394.3	P1
E2F7	ENST00000550669.5	c.1934G>C	p.Arg645Thr	missense_variant	11/11	1
E2F7	ENST00000416496.6	c.1934G>C	p.Arg645Thr	missense_variant	11/12	5

Frequencies

GnomAD3 genomes AF: 0.00605 AC: 920 AN: 152140 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0194

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00301

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000456

Gnomad OTH AF: 0.00907

GnomAD3 exomes AF: 0.00225 AC: 566 AN: 251444 Hom.: 3 AF XY: 0.00200 AC XY: 272 AN XY: 135882

Gnomad AFR exome AF: 0.0198

Gnomad AMR exome AF: 0.00254

Gnomad ASJ exome AF: 0.00635

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000633

Gnomad OTH exome AF: 0.00293

GnomAD4 exome AF: 0.00116 AC: 1697 AN: 1461880 Hom.: 9 Cov.: 31 AF XY: 0.00116 AC XY: 841 AN XY: 727238

Gnomad4 AFR exome AF: 0.0220

Gnomad4 AMR exome AF: 0.00295

Gnomad4 ASJ exome AF: 0.00582

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.0000936

Gnomad4 NFE exome AF: 0.000430

Gnomad4 OTH exome AF: 0.00252

GnomAD4 genome AF: 0.00605 AC: 921 AN: 152260 Hom.: 4 Cov.: 32 AF XY: 0.00608 AC XY: 453 AN XY: 74446

Gnomad4 AFR AF: 0.0194

Gnomad4 AMR AF: 0.00301

Gnomad4 ASJ AF: 0.00461

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.000456

Gnomad4 OTH AF: 0.00898

Alfa AF: 0.00238 Hom.: 0

Bravo AF: 0.00696

ESP6500AA AF: 0.0148 AC: 65

ESP6500EA AF: 0.00105 AC: 9

ExAC AF: 0.00245 AC: 298

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000709

EpiControl AF: 0.00130

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 12, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.61
DANN	Benign	0.17
DEOGEN2	Benign	0.020	T;.;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.054	N
LIST_S2	Benign	0.60	T;T;T
MetaRNN	Benign	0.0035	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	L;L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.20	T
PROVEAN	Benign	0.33	N;N;N
REVEL	Benign	0.013
Sift	Benign	0.54	T;T;T
Sift4G	Benign	0.57	T;T;T
Polyphen		0.0	B;B;.
Vest4		0.069
MVP		0.076
MPC		0.43
ClinPred		0.0035	T
GERP RS		-4.5
Varity_R		0.032
gMVP		0.26

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

LitVar

Other links and lift over

dbSNP: rs36110778; hg19: chr12-77421869;