chr16-2223641-A-T

Position:

• chr16-2223641-A-T

Variant summary

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

The NM_004424.5(E4F1):​c.28A>T​(p.Thr10Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000695 in 1,438,260 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: E4F1 NM_004424.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.25

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]

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=0.13388953).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
E4F1	NM_004424.5	c.28A>T	p.Thr10Ser	missense_variant	1/14	ENST00000301727.9	NP_004415.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
E4F1	ENST00000301727.9	c.28A>T	p.Thr10Ser	missense_variant	1/14	1	NM_004424.5	ENSP00000301727.4
E4F1	ENST00000564139.5	c.28A>T	p.Thr10Ser	missense_variant	1/14	1		ENSP00000457672.1
E4F1	ENST00000565090.5	c.28A>T	p.Thr10Ser	missense_variant	1/12	1		ENSP00000456760.1
E4F1	ENST00000562589.5	n.25A>T		non_coding_transcript_exon_variant	1/6	5		ENSP00000456005.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.95e-7 AC: 1 AN: 1438260 Hom.: 0 Cov.: 31 AF XY: 0.00000140 AC XY: 1 AN XY: 715992

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.04e-7

Gnomad4 OTH exome AF: 0.00

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

Aug 10, 2021

The c.28A>T (p.T10S) alteration is located in exon 1 (coding exon 1) of the E4F1 gene. This alteration results from a A to T substitution at nucleotide position 28, causing the threonine (T) at amino acid position 10 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	0.15
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	21
DANN	Benign	0.81
DEOGEN2	Benign	0.055	T;.;.
Eigen	Benign	-0.12
Eigen_PC	Benign	0.027
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.73	T;T;T
M_CAP	Benign	0.0098	T
MetaRNN	Benign	0.13	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N;.;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-0.080	N;N;N
REVEL	Benign	0.033
Sift	Benign	0.060	T;T;T
Sift4G	Benign	0.12	T;T;T
Polyphen		0.13	B;.;.
Vest4		0.20
MutPred		0.25		Gain of glycosylation at T10 (P = 0.0351);Gain of glycosylation at T10 (P = 0.0351);Gain of glycosylation at T10 (P = 0.0351);
MVP		0.52
MPC		0.38
ClinPred		0.21	T
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.12
gMVP		0.29

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: chr16-2273642;