chr1-51356789-C-T

Position:

• chr1-51356789-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001981.3(EPS15):​c.2602G>A​(p.Glu868Lys) 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: EPS15 NM_001981.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.37

Genes affected

EPS15 (HGNC:3419): (epidermal growth factor receptor pathway substrate 15) This gene encodes a protein that is part of the EGFR pathway. The protein is present at clatherin-coated pits and is involved in receptor-mediated endocytosis of EGF. Notably, this gene is rearranged with the HRX/ALL/MLL gene in acute myelogeneous leukemias. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, May 2009]

EPS15 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.051560193).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EPS15	NM_001981.3	c.2602G>A	p.Glu868Lys	missense_variant	25/25	ENST00000371733.8	NP_001972.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EPS15	ENST00000371733.8	c.2602G>A	p.Glu868Lys	missense_variant	25/25	1	NM_001981.3	ENSP00000360798.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

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 17, 2022

The c.2602G>A (p.E868K) alteration is located in exon 25 (coding exon 25) of the EPS15 gene. This alteration results from a G to A substitution at nucleotide position 2602, causing the glutamic acid (E) at amino acid position 868 to be replaced by a lysine (K). 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	0.11
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	21
DANN	Benign	0.69
DEOGEN2	Benign	0.013	T;T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.92	D;D
M_CAP	Benign	0.0069	T
MetaRNN	Benign	0.052	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.60	.;N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.45	N;N
REVEL	Benign	0.068
Sift	Benign	0.92	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0050	B;B
Vest4		0.14
MutPred		0.20		.;Gain of ubiquitination at E868 (P = 0.0039);
MVP		0.46
MPC		0.14
ClinPred		0.24	T
GERP RS		4.9
Varity_R		0.072
gMVP		0.093

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: chr1-51822461;