12-15623230-A-C

Position:

chr12-15623230-A-C

Variant summary

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

The NM_004447.6(EPS8):c.2283T>G(p.Asp761Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00794 in 1,613,380 control chromosomes in the GnomAD database, including 82 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 Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.0075 ( 5 hom., cov: 32)

Exomes 𝑓: 0.0080 ( 77 hom. )

Consequence

EPS8
NM_004447.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.221

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=0.0072618723).

BP6

Variant 12-15623230-A-C is Benign according to our data. Variant chr12-15623230-A-C is described in ClinVar as [Benign]. Clinvar id is 499499.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-15623230-A-C is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00746 (1136/152184) while in subpopulation AMR AF= 0.0143 (219/15286). AF 95% confidence interval is 0.0128. There are 5 homozygotes in gnomad4. There are 545 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPS8	NM_004447.6 linkuse as main transcript	c.2283T>G	p.Asp761Glu	missense_variant	20/21	ENST00000281172.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPS8	ENST00000281172.10 linkuse as main transcript	c.2283T>G	p.Asp761Glu	missense_variant	20/21	1	NM_004447.6	P1	Q12929-1

Frequencies

GnomAD3 genomes

AF:

0.00746

AC:

1134

AN:

152070

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0143

Gnomad ASJ

AF:

0.0297

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00561

Gnomad FIN

AF:

0.00217

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0101

Gnomad OTH

AF:

0.0110

GnomAD3 exomes

AF:

0.00721

AC:

1809

AN:

251016

Hom.:

AF XY:

0.00748

AC XY:

1015

AN XY:

135680

show subpopulations

Gnomad AFR exome

AF:

0.00135

Gnomad AMR exome

AF:

0.00530

Gnomad ASJ exome

AF:

0.0250

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00772

Gnomad FIN exome

AF:

0.00263

Gnomad NFE exome

AF:

0.00880

Gnomad OTH exome

AF:

0.00997

GnomAD4 exome

AF:

0.00799

AC:

11678

AN:

1461196

Hom.:

Cov.:

AF XY:

0.00805

AC XY:

5853

AN XY:

726920

show subpopulations

Gnomad4 AFR exome

AF:

0.00102

Gnomad4 AMR exome

AF:

0.00604

Gnomad4 ASJ exome

AF:

0.0260

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00769

Gnomad4 FIN exome

AF:

0.00219

Gnomad4 NFE exome

AF:

0.00838

Gnomad4 OTH exome

AF:

0.00863

GnomAD4 genome

AF:

0.00746

AC:

1136

AN:

152184

Hom.:

Cov.:

AF XY:

0.00732

AC XY:

545

AN XY:

74424

show subpopulations

Gnomad4 AFR

AF:

0.00120

Gnomad4 AMR

AF:

0.0143

Gnomad4 ASJ

AF:

0.0297

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00561

Gnomad4 FIN

AF:

0.00217

Gnomad4 NFE

AF:

0.0101

Gnomad4 OTH

AF:

0.0113

Alfa

AF:

0.0101

Hom.:

Bravo

AF:

0.00793

TwinsUK

AF:

0.0111

AC:

ALSPAC

AF:

0.0122

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.0117

AC:

101

ExAC

AF:

0.00736

AC:

893

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.00993

EpiControl

AF:

0.00914

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 04, 2018	This variant is associated with the following publications: (PMID: 26721930) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 15, 2023	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	EPS8: BS1, BS2 -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 26, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 23, 2017	p.Asp761Glu in exon 20 of EPS8: This variant is not expected to have clinical si gnificance because it has been identified in 0.98% (652/66712) of European chrom osomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ; dbSNP rs7137185). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.61

CADD

Benign

4.9

DANN

Benign

0.85

DEOGEN2

Benign

0.11

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

Eigen

Benign

-0.65

Eigen_PC

Benign

-0.44

FATHMM_MKL

Benign

0.69

LIST_S2

Benign

0.53

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

MetaRNN

Benign

0.0073

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

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.33

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

MutationTaster

Benign

0.98

D;D;D;D;D

PrimateAI

Uncertain

0.56

PROVEAN

Benign

0.15

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

REVEL

Benign

0.15

Sift

Benign

0.99

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

Sift4G

Benign

0.52

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

Polyphen

0.0

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

Vest4

0.22

MutPred

0.18

Gain of ubiquitination at K760 (P = 0.0945);Gain of ubiquitination at K760 (P = 0.0945);Gain of ubiquitination at K760 (P = 0.0945);Gain of ubiquitination at K760 (P = 0.0945);.;Gain of ubiquitination at K760 (P = 0.0945);Gain of ubiquitination at K760 (P = 0.0945);Gain of ubiquitination at K760 (P = 0.0945);Gain of ubiquitination at K760 (P = 0.0945);.;Gain of ubiquitination at K760 (P = 0.0945);Gain of ubiquitination at K760 (P = 0.0945);.;.;

MVP

0.31

MPC

0.11

ClinPred

0.0059

GERP RS

1.9

Varity_R

0.042

gMVP

0.24

Splicing

Name

Calibrated prediction

Score

Prediction

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