NM_001950.4:c.634C>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001950.4(E2F4):​c.634C>T​(p.Pro212Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

E2F4
NM_001950.4 missense

Scores

14
5

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.91
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
E2F4NM_001950.4 linkc.634C>T p.Pro212Ser missense_variant Exon 6 of 10 ENST00000379378.8 NP_001941.2 Q16254

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
E2F4ENST00000379378.8 linkc.634C>T p.Pro212Ser missense_variant Exon 6 of 10 1 NM_001950.4 ENSP00000368686.3 Q16254

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461888
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
727244
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jan 19, 2022
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.634C>T (p.P212S) alteration is located in exon 6 (coding exon 6) of the E2F4 gene. This alteration results from a C to T substitution at nucleotide position 634, causing the proline (P) at amino acid position 212 to be replaced by a serine (S). 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
0.28
BayesDel_addAF
Uncertain
0.15
D
BayesDel_noAF
Uncertain
-0.020
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.45
T
Eigen
Uncertain
0.26
Eigen_PC
Uncertain
0.33
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Uncertain
0.94
D
M_CAP
Uncertain
0.11
D
MetaRNN
Uncertain
0.42
T
MetaSVM
Uncertain
0.058
D
MutationAssessor
Benign
1.7
L
PrimateAI
Uncertain
0.59
T
PROVEAN
Uncertain
-4.3
D
REVEL
Uncertain
0.54
Sift
Benign
0.036
D
Sift4G
Benign
0.13
T
Polyphen
0.65
P
Vest4
0.56
MutPred
0.21
Gain of phosphorylation at P212 (P = 0.0206);
MVP
0.95
MPC
0.32
ClinPred
0.99
D
GERP RS
3.9
Varity_R
0.28
gMVP
0.53

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: chr16-67228709; COSMIC: COSV58873905; COSMIC: COSV58873905; API