NM_004447.6:c.2230G>A

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_004447.6(EPS8):c.2230G>A(p.Val744Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00253 in 1,569,038 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0024 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0025 ( 6 hom. )

Consequence

EPS8
NM_004447.6 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 2.84

Variant links:

Genes affected

EPS8 (HGNC:3420): (EGFR pathway substrate 8, signaling adaptor) This gene encodes a member of the EPS8 family. This protein contains one PH domain and one SH3 domain. It functions as part of the EGFR pathway, though its exact role has not been determined. Highly similar proteins in other organisms are involved in the transduction of signals from Ras to Rac and growth factor-mediated actin remodeling. Alternate transcriptional splice variants of this gene have been observed but have not been thoroughly characterized. [provided by RefSeq, Jul 2008]

EPS8 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008447826).

BP6

Variant 12-15623283-C-T is Benign according to our data. Variant chr12-15623283-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 506478.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00238 (349/146848) while in subpopulation NFE AF= 0.00372 (251/67502). AF 95% confidence interval is 0.00334. There are 0 homozygotes in gnomad4. There are 161 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPS8	NM_004447.6 link	c.2230G>A	p.Val744Ile	missense_variant	Exon 20 of 21	ENST00000281172.10	NP_004438.3	Q12929-1B4E3T6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPS8	ENST00000281172.10 link	c.2230G>A	p.Val744Ile	missense_variant	Exon 20 of 21	1	NM_004447.6	ENSP00000281172.5		Q12929-1

Frequencies

GnomAD3 genomes

AF:

0.00238

AC:

349

AN:

146746

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000687

Gnomad AMI

AF:

0.00442

Gnomad AMR

AF:

0.00313

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000611

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00372

Gnomad OTH

AF:

0.00392

GnomAD3 exomes

AF:

0.00205

AC:

438

AN:

213728

Hom.:

AF XY:

0.00200

AC XY:

233

AN XY:

116478

show subpopulations

Gnomad AFR exome

AF:

0.000342

Gnomad AMR exome

AF:

0.00230

Gnomad ASJ exome

AF:

0.00248

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00104

Gnomad NFE exome

AF:

0.00307

Gnomad OTH exome

AF:

0.00429

GnomAD4 exome

AF:

0.00254

AC:

3615

AN:

1422190

Hom.:

Cov.:

AF XY:

0.00252

AC XY:

1780

AN XY:

707702

show subpopulations

Gnomad4 AFR exome

AF:

0.000454

Gnomad4 AMR exome

AF:

0.00247

Gnomad4 ASJ exome

AF:

0.00258

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000125

Gnomad4 FIN exome

AF:

0.00116

Gnomad4 NFE exome

AF:

0.00294

Gnomad4 OTH exome

AF:

0.00285

GnomAD4 genome

AF:

0.00238

AC:

349

AN:

146848

Hom.:

Cov.:

AF XY:

0.00225

AC XY:

161

AN XY:

71598

show subpopulations

Gnomad4 AFR

AF:

0.000685

Gnomad4 AMR

AF:

0.00313

Gnomad4 ASJ

AF:

0.00202

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000611

Gnomad4 NFE

AF:

0.00372

Gnomad4 OTH

AF:

0.00388

Alfa

AF:

0.00305

Hom.:

Bravo

AF:

0.00233

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00234

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00326

AC:

ExAC

AF:

0.00185

AC:

224

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Mar 25, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified

Benign:1

May 07, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Val744Ile in exon 20 of EPS8: This variant is classified as likely benign beca use it has been identified in 0.3% (355/114830) of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs7 7967764). In addition, computational prediction tools and conservation analyses do not suggest a high likelihood of impact to the protein. ACMG/AMP Criteria ap plied: BS1, BP4. -

EPS8-related disorder

Benign:1

Jan 19, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.25

T;T;T;T;.;T;T;T;T;.;T;T;.;.

Eigen

Benign

0.097

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.92

.;.;.;.;D;.;.;.;.;D;.;D;.;D

MetaRNN

Benign

0.0084

T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

L;L;L;L;.;L;L;L;L;.;L;L;.;.

PrimateAI

Benign

0.46

PROVEAN

Benign

-0.56

N;.;N;.;.;.;.;.;.;.;.;N;N;N

REVEL

Benign

0.13

Sift

Benign

0.047

D;.;D;.;.;.;.;.;.;.;.;D;D;D

Sift4G

Benign

0.15

T;.;T;.;.;.;.;.;.;.;.;T;D;D

Polyphen

0.16

B;B;B;B;.;B;B;B;B;.;B;B;.;.

Vest4

0.18

MVP

0.30

MPC

0.29

ClinPred

0.015

GERP RS

5.7

Varity_R

0.097

gMVP

0.38

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

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