dbSNP rs777257044: EPS15:p.Gly627Val (chr1-51402437-C-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001981.3(EPS15):c.1880G>T(p.Gly627Val) variant causes a missense, splice region 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. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G627D) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

EPS15
NM_001981.3 missense, splice_region

Scores

Splicing: ADA: 0.08945

Clinical Significance

Not reported in ClinVar

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2748559).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPS15	NM_001981.3 link	c.1880G>T	p.Gly627Val	missense_variant, splice_region_variant	Exon 18 of 25	ENST00000371733.8	NP_001972.1	P42566-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPS15	ENST00000371733.8 link	c.1880G>T	p.Gly627Val	missense_variant, splice_region_variant	Exon 18 of 25	1	NM_001981.3	ENSP00000360798.3		P42566-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

229832

AF XY:

0.00

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1381324

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

689244

African (AFR)

AF:

0.00

AC:

AN:

30778

American (AMR)

AF:

0.00

AC:

AN:

38738

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24574

East Asian (EAS)

AF:

0.00

AC:

AN:

38468

South Asian (SAS)

AF:

0.00

AC:

AN:

77328

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52188

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4980

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1057206

Other (OTH)

AF:

0.00

AC:

AN:

57064

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Benign

0.011

BayesDel_noAF

Benign

-0.22

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.067

T;T

Eigen

Uncertain

0.33

Eigen_PC

Uncertain

0.35

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.97

D;D

M_CAP

Benign

0.022

MetaRNN

Benign

0.27

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

2.0

.;M

PhyloP100

2.7

PrimateAI

Uncertain

0.68

PROVEAN

Uncertain

-3.8

D;D

REVEL

Benign

0.13

Sift

Uncertain

0.024

D;D

Sift4G

Uncertain

0.047

D;D

Polyphen

0.98

D;B

Vest4

0.58

MutPred

0.16

.;Gain of glycosylation at S622 (P = 0.1475);

MVP

0.55

MPC

0.24

ClinPred

0.94

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.60

gMVP

0.24

Mutation Taster

=73/27

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.089

dbscSNV1_RF

Benign

0.29

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

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