12-15621387-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004447.6(EPS8):c.2399G>A(p.Arg800Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0000131 in 1,604,520 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000013 ( 0 hom. )

Consequence

EPS8
NM_004447.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.94

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 Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.23100364).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPS8	NM_004447.6 linkuse as main transcript	c.2399G>A	p.Arg800Gln	missense_variant	21/21	ENST00000281172.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPS8	ENST00000281172.10 linkuse as main transcript	c.2399G>A	p.Arg800Gln	missense_variant	21/21	1	NM_004447.6	P1	Q12929-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000166

AC:

AN:

241210

Hom.:

AF XY:

0.00000765

AC XY:

AN XY:

130676

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000624

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000573

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000906

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000131

AC:

AN:

1452386

Hom.:

Cov.:

AF XY:

0.0000111

AC XY:

AN XY:

722396

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000232

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000257

Gnomad4 SAS exome

AF:

0.0000237

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000126

Gnomad4 OTH exome

AF:

0.0000167

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152134

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74316

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ExAC

AF:

0.0000247

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 28, 2023

The c.2399G>A (p.R800Q) alteration is located in exon 21 (coding exon 20) of the EPS8 gene. This alteration results from a G to A substitution at nucleotide position 2399, causing the arginine (R) at amino acid position 800 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.67

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.22

Cadd

Uncertain

Dann

Uncertain

1.0

DEOGEN2

Benign

0.14

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

Eigen

Uncertain

0.35

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Pathogenic

1.0

M_CAP

Benign

0.020

MetaRNN

Benign

0.23

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

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

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

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-0.59

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

REVEL

Benign

0.16

Sift

Benign

0.27

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

Sift4G

Benign

0.29

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

Polyphen

0.96

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

Vest4

0.63

MutPred

0.23

Loss of MoRF binding (P = 0.0524);Loss of MoRF binding (P = 0.0524);Loss of MoRF binding (P = 0.0524);Loss of MoRF binding (P = 0.0524);.;Loss of MoRF binding (P = 0.0524);Loss of MoRF binding (P = 0.0524);Loss of MoRF binding (P = 0.0524);Loss of MoRF binding (P = 0.0524);.;Loss of MoRF binding (P = 0.0524);Loss of MoRF binding (P = 0.0524);.;.;

MVP

0.67

MPC

0.61

ClinPred

0.67

GERP RS

5.5

Varity_R

0.14

gMVP

0.43

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