16-2228373-T-A

Position:

• chr16-2228373-T-A

Variant summary

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

The NM_004424.5(E4F1):​c.159T>A​(p.Asp53Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. 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 (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: E4F1 NM_004424.5 missense, splice_region
• Scores: Splicing: ADA: 0.003663
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.44

Genes affected

E4F1 (HGNC:3121): (E4F transcription factor 1) The zinc finger protein encoded by this gene is one of several cellular transcription factors whose DNA-binding activities are regulated through the action of adenovirus E1A. A 50-kDa amino-terminal product is generated from the full-length protein through proteolytic cleavage. The protein is differentially regulated by E1A-induced phosphorylation. The full-length gene product represses transcription from the E4 promoter in the absence of E1A, while the 50-kDa form acts as a transcriptional activator in its presence. Alternative splicing results in multiple transcripts encoding different proteins. [provided by RefSeq, Jan 2014]

E4F1 (HGNC:):

ACMG classification

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/exons	MANE	Protein	UniProt
E4F1	NM_004424.5	c.159T>A	p.Asp53Glu	missense_variant, splice_region_variant	2/14	ENST00000301727.9	NP_004415.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
E4F1	ENST00000301727.9	c.159T>A	p.Asp53Glu	missense_variant, splice_region_variant	2/14	1	NM_004424.5	ENSP00000301727.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 02, 2022

The c.159T>A (p.D53E) alteration is located in exon 2 (coding exon 2) of the E4F1 gene. This alteration results from a T to A substitution at nucleotide position 159, causing the aspartic acid (D) at amino acid position 53 to be replaced by a glutamic acid (E). 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	0.24
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Uncertain	23
DANN	Benign	0.93
DEOGEN2	Benign	0.067	T;.;.;T
Eigen	Benign	0.18
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.72	T;T;T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.22	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.81	L;.;.;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.92	N;N;N;N
REVEL	Benign	0.14
Sift	Pathogenic	0.0	D;D;D;T
Sift4G	Benign	0.071	T;D;T;D
Polyphen		0.99	D;.;.;.
Vest4		0.42
MutPred		0.35		Gain of glycosylation at P48 (P = 0.1346);Gain of glycosylation at P48 (P = 0.1346);Gain of glycosylation at P48 (P = 0.1346);.;
MVP		0.70
MPC		1.0
ClinPred		0.64	D
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.21
gMVP		0.18

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0037
SpliceAI score (max)		0.48		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.48		Position offset: -1

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: chr16-2278374;