16-2229636-T-C

Position:

• chr16-2229636-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004424.5(E4F1):​c.376T>C​(p.Ser126Pro) variant causes a missense 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. 14/21 in silico tools predict 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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.739

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09253365).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
E4F1	NM_004424.5	c.376T>C	p.Ser126Pro	missense_variant	3/14	ENST00000301727.9	NP_004415.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
E4F1	ENST00000301727.9	c.376T>C	p.Ser126Pro	missense_variant	3/14	1	NM_004424.5	ENSP00000301727.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

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

Jun 13, 2024

The c.376T>C (p.S126P) alteration is located in exon 3 (coding exon 3) of the E4F1 gene. This alteration results from a T to C substitution at nucleotide position 376, causing the serine (S) at amino acid position 126 to be replaced by a proline (P). 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	0.14
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	14
DANN	Uncertain	0.98
DEOGEN2	Benign	0.088	T;.;.;T
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.74	T;T;T;T
M_CAP	Benign	0.0041	T
MetaRNN	Benign	0.093	T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.5	L;.;.;.
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.6	N;N;N;N
REVEL	Benign	0.046
Sift	Benign	0.098	T;T;T;T
Sift4G	Benign	0.14	T;T;T;T
Polyphen		0.31	B;.;.;.
Vest4		0.22
MutPred		0.38		Loss of glycosylation at S126 (P = 0.0761);Loss of glycosylation at S126 (P = 0.0761);Loss of glycosylation at S126 (P = 0.0761);.;
MVP		0.41
MPC		0.47
ClinPred		0.037	T
GERP RS		-1.1
Varity_R		0.18
gMVP		0.42

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: chr16-2279637;