Variant 1-51402437-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001981.3(EPS15):c.1880G>A(p.Gly627Asp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,381,324 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000043 ( 0 hom. )

Consequence

EPS15
NM_001981.3 missense, splice_region

Scores

Splicing: ADA: 0.01658

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.66

Variant links:

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 links:

EPS15 (HGNC:):

EPS15 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.16215837).

BS2

High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EPS15	NM_001981.3 linkuse as main transcript	c.1880G>A	p.Gly627Asp	missense_variant, splice_region_variant	18/25	ENST00000371733.8	NP_001972.1	P42566-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EPS15	ENST00000371733.8 linkuse as main transcript	c.1880G>A	p.Gly627Asp	missense_variant, splice_region_variant	18/25	1	NM_001981.3	ENSP00000360798.3		P42566-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000435

AC:

AN:

229832

Hom.:

AF XY:

0.00000804

AC XY:

AN XY:

124450

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000383

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000434

AC:

AN:

1381324

Hom.:

Cov.:

AF XY:

0.00000725

AC XY:

AN XY:

689242

show subpopulations

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:

0.0000647

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.46e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 13, 2023

The c.1880G>A (p.G627D) alteration is located in exon 18 (coding exon 18) of the EPS15 gene. This alteration results from a G to A substitution at nucleotide position 1880, causing the glycine (G) at amino acid position 627 to be replaced by an aspartic acid (D). 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

0.23

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.30

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.027

T;T

Eigen

Benign

0.11

Eigen_PC

Benign

0.20

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.89

D;D

M_CAP

Benign

0.014

MetaRNN

Benign

0.16

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.2

.;L

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-2.0

N;N

REVEL

Benign

0.11

Sift

Benign

0.18

T;T

Sift4G

Benign

0.35

T;T

Polyphen

1.0

D;B

Vest4

0.26

MutPred

0.14

.;Gain of glycosylation at S622 (P = 0.0724);

MVP

0.54

MPC

0.17

ClinPred

0.40

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.26

gMVP

0.15

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.017

dbscSNV1_RF

Benign

0.23

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over