NM_004447.6:c.2352G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_004447.6(EPS8):c.2352G>A(p.Leu784Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0487 in 1,604,462 control chromosomes in the GnomAD database, including 10,231 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L784L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.15 ( 5081 hom., cov: 32)

Exomes 𝑓: 0.038 ( 5150 hom. )

Consequence

EPS8
NM_004447.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -0.489

Publications

7 publications found

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 Gene-Disease associations (from GenCC):

autosomal recessive nonsyndromic hearing loss 102
Inheritance: AR Classification: STRONG, MODERATE Submitted by: ClinGen, PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae)
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

EPS8 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.45).

BP6

Variant 12-15623161-C-T is Benign according to our data. Variant chr12-15623161-C-T is described in ClinVar as Benign. ClinVar VariationId is 508137.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.489 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.48 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPS8	NM_004447.6 link	c.2352G>A	p.Leu784Leu	synonymous_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.2352G>A	p.Leu784Leu	synonymous_variant	Exon 20 of 21	1	NM_004447.6	ENSP00000281172.5		Q12929-1

Frequencies

GnomAD3 genomes

AF:

0.154

AC:

23361

AN:

151970

Hom.:

5072

Cov.:

show subpopulations

Gnomad AFR

AF:

0.485

Gnomad AMI

AF:

0.0132

Gnomad AMR

AF:

0.0655

Gnomad ASJ

AF:

0.0196

Gnomad EAS

AF:

0.0415

Gnomad SAS

AF:

0.0459

Gnomad FIN

AF:

0.00245

Gnomad MID

AF:

0.0665

Gnomad NFE

AF:

0.0222

Gnomad OTH

AF:

0.115

GnomAD2 exomes

AF:

0.0578

AC:

13963

AN:

241568

AF XY:

0.0493

show subpopulations

Gnomad AFR exome

AF:

0.495

Gnomad AMR exome

AF:

0.0316

Gnomad ASJ exome

AF:

0.0244

Gnomad EAS exome

AF:

0.0433

Gnomad FIN exome

AF:

0.00397

Gnomad NFE exome

AF:

0.0223

Gnomad OTH exome

AF:

0.0355

GnomAD4 exome

AF:

0.0376

AC:

54669

AN:

1452376

Hom.:

5150

Cov.:

AF XY:

0.0360

AC XY:

26017

AN XY:

722048

show subpopulations

African (AFR)

AF:

0.512

AC:

16777

AN:

32742

American (AMR)

AF:

0.0352

AC:

1500

AN:

42638

Ashkenazi Jewish (ASJ)

AF:

0.0238

AC:

613

AN:

25764

East Asian (EAS)

AF:

0.0354

AC:

1401

AN:

39606

South Asian (SAS)

AF:

0.0452

AC:

3774

AN:

83474

European-Finnish (FIN)

AF:

0.00503

AC:

268

AN:

53294

Middle Eastern (MID)

AF:

0.0606

AC:

346

AN:

5710

European-Non Finnish (NFE)

AF:

0.0241

AC:

26786

AN:

1109170

Other (OTH)

AF:

0.0534

AC:

3204

AN:

59978

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

2117

4234

6351

8468

10585

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1322

2644

3966

5288

6610

<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

AF:

0.154

AC:

23404

AN:

152086

Hom.:

5081

Cov.:

AF XY:

0.148

AC XY:

11020

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.485

AC:

20095

AN:

41414

American (AMR)

AF:

0.0652

AC:

997

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0196

AC:

AN:

3470

East Asian (EAS)

AF:

0.0414

AC:

214

AN:

5170

South Asian (SAS)

AF:

0.0458

AC:

221

AN:

4828

European-Finnish (FIN)

AF:

0.00245

AC:

AN:

10594

Middle Eastern (MID)

AF:

0.0680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0222

AC:

1510

AN:

67998

Other (OTH)

AF:

0.114

AC:

241

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

669

1338

2007

2676

3345

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

196

392

588

784

980

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0727

Hom.:

1318

Bravo

AF:

0.173

Asia WGS

AF:

0.0640

AC:

225

AN:

3478

EpiCase

AF:

0.0243

EpiControl

AF:

0.0256

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

May 24, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

May 09, 2017

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Aug 23, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Leu784Leu in exon 20 of EPS8: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue, is not located withi n the splice consensus sequence, and has been identified in 48.80% (5077/10404) of African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.br oadinstitute.org; dbSNP rs1126786). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.45

CADD

Benign

3.7

(source)

DANN

Benign

0.69

PhyloP100

-0.49

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=94/6

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over