1-51356789-C-T

Variant names:

• chr1-51356789-C-T
• NM_001981.3:c.2602G>A

Variant summary

Our verdict is Likely benign. The variant received -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. 16/22 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
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001981.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPS15	NM_001981.3	MANE Select	c.2602G>A	p.Glu868Lys	missense	Exon 25 of 25	NP_001972.1	P42566-1
	EPS15	NM_001410797.1		c.2713G>A	p.Glu905Lys	missense	Exon 25 of 25	NP_001397726.1	A0A994J5A3
	EPS15	NM_001410796.1		c.2512G>A	p.Glu838Lys	missense	Exon 24 of 24	NP_001397725.1	A0A994J5J3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPS15	ENST00000371733.8	TSL:1 MANE Select	c.2602G>A	p.Glu868Lys	missense	Exon 25 of 25	ENSP00000360798.3	P42566-1
	EPS15	ENST00000371730.6	TSL:1	c.2200G>A	p.Glu734Lys	missense	Exon 23 of 23	ENSP00000360795.2	B1AUU8
	EPS15	ENST00000706292.1		c.2713G>A	p.Glu905Lys	missense	Exon 25 of 25	ENSP00000516336.1	A0A994J5A3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.0069	T
MetaRNN	Benign	0.052	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.60	N
PhyloP100		3.4
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.45	N
REVEL	Benign	0.068
Sift	Benign	0.92	T
Sift4G	Benign	1.0	T
Polyphen		0.0050	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
Mutation Taster		=85/15	polymorphism

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

Other links and lift over

hg19: chr1-51822461;