chr16-67194687-G-T

Variant names:

• chr16-67194687-G-T
• rs145929720
• NM_001950.4:c.515G>T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001950.4(E2F4):​c.515G>T​(p.Gly172Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000503 in 1,610,808 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00029 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00053 (0 hom.)
• Consequence: E2F4 NM_001950.4 missense, splice_region
• Scores: Splicing: ADA: 0.005328
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.86

Genes affected

E2F4 (HGNC:3118): (E2F transcription factor 4) The protein encoded by this gene is a member of the E2F family of transcription factors. The E2F family plays a crucial role in the control of cell cycle and action of tumor suppressor proteins and is also a target of the transforming proteins of small DNA tumor viruses. The E2F proteins contain several evolutionally conserved domains found in most members of the family. These domains include a DNA binding domain, a dimerization domain which determines interaction with the differentiation regulated transcription factor proteins (DP), a transactivation domain enriched in acidic amino acids, and a tumor suppressor protein association domain which is embedded within the transactivation domain. This protein binds to all three of the tumor suppressor proteins pRB, p107 and p130, but with higher affinity to the last two. It plays an important role in the suppression of proliferation-associated genes, and its gene mutation and increased expression may be associated with human cancer. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.12224132).
• BS2: High AC in GnomAd4 at 44 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
E2F4	NM_001950.4	c.515G>T	p.Gly172Val	missense_variant, splice_region_variant	Exon 6 of 10	ENST00000379378.8	NP_001941.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
E2F4	ENST00000379378.8	c.515G>T	p.Gly172Val	missense_variant, splice_region_variant	Exon 6 of 10	1	NM_001950.4	ENSP00000368686.3

Frequencies

GnomAD3 genomes AF: 0.000289 AC: 44 AN: 152186 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000196 AC: 49 AN: 250298 Hom.: 0 AF XY: 0.000199 AC XY: 27 AN XY: 135358

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000417

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000526 AC: 767 AN: 1458622 Hom.: 0 Cov.: 31 AF XY: 0.000502 AC XY: 364 AN XY: 724850

Gnomad4 AFR exome AF: 0.000180

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000675

Gnomad4 OTH exome AF: 0.000133

GnomAD4 genome AF: 0.000289 AC: 44 AN: 152186 Hom.: 0 Cov.: 32 AF XY: 0.000215 AC XY: 16 AN XY: 74332

Gnomad4 AFR AF: 0.0000965

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000390 Hom.: 0

Bravo AF: 0.000253

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000181 AC: 22

EpiCase AF: 0.000382

EpiControl AF: 0.000356

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 14, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.515G>T (p.G172V) alteration is located in exon 6 (coding exon 6) of the E2F4 gene. This alteration results from a G to T substitution at nucleotide position 515, causing the glycine (G) at amino acid position 172 to be replaced by a valine (V). 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	0.19
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.27
CADD	Pathogenic	26
DANN	Benign	0.93
DEOGEN2	Benign	0.13	T
Eigen	Benign	0.0036
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.44	T
MutationAssessor	Benign	1.4	L
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-2.5	N
REVEL	Benign	0.25
Sift	Benign	0.11	T
Sift4G	Benign	0.13	T
Polyphen		0.067	B
Vest4		0.20
MVP		0.99
MPC		0.25
ClinPred		0.083	T
GERP RS		5.7
Varity_R		0.37
gMVP		0.40

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0053
dbscSNV1_RF	Benign	0.062
SpliceAI score (max)		0.030		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: rs145929720; hg19: chr16-67228590;