Genetic Variant NM_001981.3:c.2569G>A (chr1-51356822-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_001981.3(EPS15):c.2569G>A(p.Glu857Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000548 in 1,461,066 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

EPS15
NM_001981.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.00

Publications

1 publications found

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAdExome4 at 8 AD gene.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EPS15	NM_001981.3	MANE Select	c.2569G>A	p.Glu857Lys	missense	Exon 25 of 25	NP_001972.1	P42566-1
EPS15	NM_001410797.1		c.2680G>A	p.Glu894Lys	missense	Exon 25 of 25	NP_001397726.1	A0A994J5A3
EPS15	NM_001410796.1		c.2479G>A	p.Glu827Lys	missense	Exon 24 of 24	NP_001397725.1	A0A994J5J3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EPS15	ENST00000371733.8	TSL:1 MANE Select	c.2569G>A	p.Glu857Lys	missense	Exon 25 of 25	ENSP00000360798.3	P42566-1
EPS15	ENST00000371730.6	TSL:1	c.2167G>A	p.Glu723Lys	missense	Exon 23 of 23	ENSP00000360795.2	B1AUU8
EPS15	ENST00000706292.1		c.2680G>A	p.Glu894Lys	missense	Exon 25 of 25	ENSP00000516336.1	A0A994J5A3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000801

AC:

AN:

249602

AF XY:

0.0000148

show subpopulations

Gnomad AFR exome

AF:

0.0000617

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

AF:

0.00000548

AC:

AN:

1461066

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

726864

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33438

American (AMR)

AF:

0.00

AC:

AN:

44634

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26108

East Asian (EAS)

AF:

0.00

AC:

AN:

39644

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86158

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53354

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00000540

AC:

AN:

1111616

Other (OTH)

AF:

0.00

AC:

AN:

60350

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.62

BayesDel_addAF

Benign

0.0060

BayesDel_noAF

Uncertain

-0.050

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.021

Eigen

Pathogenic

0.77

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.039

MetaRNN

Uncertain

0.58

MetaSVM

Benign

-0.67

MutationAssessor

Uncertain

2.3

PhyloP100

7.0

PrimateAI

Uncertain

0.78

PROVEAN

Benign

-1.8

REVEL

Benign

0.19

Sift

Benign

0.14

Sift4G

Benign

0.094

Polyphen

1.0

Vest4

0.75

MutPred

0.17

Gain of ubiquitination at E857 (P = 0.006)

MVP

0.77

MPC

0.62

ClinPred

0.94

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.21

gMVP

0.44

Mutation Taster

=42/58

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over