chr8-85213795-A-T
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Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3BS2
The NM_001951.4(E2F5):c.974A>T(p.Tyr325Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000273 in 1,613,266 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000027 ( 0 hom. )
Consequence
E2F5
NM_001951.4 missense
NM_001951.4 missense
Scores
3
12
4
Clinical Significance
Conservation
PhyloP100: 8.41
Genes affected
E2F5 (HGNC:3119): (E2F transcription factor 5) 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 evolutionarily conserved domains that are present 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 is differentially phosphorylated and is expressed in a wide variety of human tissues. It has higher identity to E2F4 than to other family members. Both this protein and E2F4 interact with tumor suppressor proteins p130 and p107, but not with pRB. Alternative splicing results in multiple variants encoding different isoforms. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -3 ACMG points.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.792
BS2
High AC in GnomAdExome4 at 40 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
E2F5 | NM_001951.4 | c.974A>T | p.Tyr325Phe | missense_variant | 8/8 | ENST00000416274.7 | NP_001942.2 | |
E2F5 | NM_001083588.2 | c.971A>T | p.Tyr324Phe | missense_variant | 8/8 | NP_001077057.1 | ||
E2F5 | NM_001083589.2 | c.491A>T | p.Tyr164Phe | missense_variant | 8/8 | NP_001077058.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
E2F5 | ENST00000416274.7 | c.974A>T | p.Tyr325Phe | missense_variant | 8/8 | 1 | NM_001951.4 | ENSP00000398124 | P4 |
Frequencies
GnomAD3 genomes AF: 0.0000263 AC: 4AN: 152126Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000321 AC: 8AN: 249076Hom.: 0 AF XY: 0.0000296 AC XY: 4AN XY: 135108
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GnomAD4 exome AF: 0.0000274 AC: 40AN: 1461140Hom.: 0 Cov.: 30 AF XY: 0.0000344 AC XY: 25AN XY: 726866
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GnomAD4 genome AF: 0.0000263 AC: 4AN: 152126Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74308
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 10, 2022 | The c.974A>T (p.Y325F) alteration is located in exon 8 (coding exon 8) of the E2F5 gene. This alteration results from a A to T substitution at nucleotide position 974, causing the tyrosine (Y) at amino acid position 325 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
.;T;.;.;T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D;D
M_CAP
Benign
T
MetaRNN
Pathogenic
D;D;D;D;D
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
.;M;.;.;.
MutationTaster
Benign
D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D;D;D
REVEL
Pathogenic
Sift
Benign
T;T;T;D;D
Sift4G
Uncertain
D;D;T;T;T
Polyphen
D;P;.;D;.
Vest4
MutPred
0.61
.;Loss of phosphorylation at Y325 (P = 0.0325);.;.;.;
MVP
MPC
0.43
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at