chr12-15624275-G-A

Position:

chr12-15624275-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBS1_Supporting

The NM_004447.6(EPS8):c.2177C>T(p.Thr726Ile) variant causes a missense change. The variant allele was found at a frequency of 0.000698 in 1,613,892 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00040 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00073 ( 1 hom. )

Consequence

EPS8
NM_004447.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 5.91

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 Likely_benign. Variant got -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.13251984).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0004 (61/152314) while in subpopulation NFE AF= 0.000809 (55/68024). AF 95% confidence interval is 0.000638. There are 0 homozygotes in gnomad4. There are 24 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPS8	NM_004447.6 linkuse as main transcript	c.2177C>T	p.Thr726Ile	missense_variant	19/21	ENST00000281172.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPS8	ENST00000281172.10 linkuse as main transcript	c.2177C>T	p.Thr726Ile	missense_variant	19/21	1	NM_004447.6	P1	Q12929-1

Frequencies

GnomAD3 genomes

AF:

0.000401

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000808

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000382

AC:

AN:

251084

Hom.:

AF XY:

0.000383

AC XY:

AN XY:

135686

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.0000579

Gnomad ASJ exome

AF:

0.0000993

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000775

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000729

AC:

1065

AN:

1461578

Hom.:

Cov.:

AF XY:

0.000712

AC XY:

518

AN XY:

727074

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.0000894

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000749

Gnomad4 NFE exome

AF:

0.000928

Gnomad4 OTH exome

AF:

0.000265

GnomAD4 genome

AF:

0.000400

AC:

AN:

152314

Hom.:

Cov.:

AF XY:

0.000322

AC XY:

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.0000962

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.000809

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000692

Hom.:

Bravo

AF:

0.000359

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00116

AC:

ExAC

AF:

0.000404

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.000982

EpiControl

AF:

0.000949

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 13, 2022	This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 726 of the EPS8 protein (p.Thr726Ile). This variant is present in population databases (rs150904526, gnomAD 0.08%). This variant has not been reported in the literature in individuals affected with EPS8-related conditions. ClinVar contains an entry for this variant (Variation ID: 517643). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt EPS8 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 27, 2022	In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Dec 05, 2017

The p.Thr726Ile variant in EPS8 has not been previously reported in individuals with hearing loss, but has been identified in 0.08% (100/126428) of European chr omosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitut e.org; dbSNP rs150904526). Although this variant has been seen in the general po pulation, its frequency is not high enough to rule out a pathogenic role. Comput ational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Thr726Ile variant is uncertain. ACMG/AMP Criteria applied: None -

Autosomal recessive nonsyndromic hearing loss 102

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 09, 2022

- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 08, 2022

The c.2177C>T (p.T726I) alteration is located in exon 19 (coding exon 18) of the EPS8 gene. This alteration results from a C to T substitution at nucleotide position 2177, causing the threonine (T) at amino acid position 726 to be replaced by an isoleucine (I). 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

Benign

0.19

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.78

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

Eigen

Benign

0.035

Eigen_PC

Benign

0.12

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.66

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

M_CAP

Benign

0.010

MetaRNN

Benign

0.13

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

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.7

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

MutationTaster

Benign

0.98

D;D;D;D;D

PrimateAI

Benign

0.48

PROVEAN

Uncertain

-2.5

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

REVEL

Benign

0.15

Sift

Benign

0.059

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

Sift4G

Uncertain

0.048

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

Polyphen

0.11

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

Vest4

0.28

MVP

0.27

MPC

0.13

ClinPred

0.034

GERP RS

5.4

Varity_R

0.098

gMVP

0.66

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