dbSNP rs11102001: EPS8L3:p.Pro356Ser (chr1-109757069-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_133181.4(EPS8L3):c.1066C>T(p.Pro356Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0785 in 1,613,934 control chromosomes in the GnomAD database, including 8,986 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.15 ( 3233 hom., cov: 32)

Exomes 𝑓: 0.071 ( 5753 hom. )

Consequence

EPS8L3
NM_133181.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.203

Variant links:

Genes affected

EPS8L3 (HGNC:21297): (EPS8 signaling adaptor L3) This gene encodes a protein that is related to epidermal growth factor receptor pathway substrate 8 (EPS8), a substrate for the epidermal growth factor receptor. The function of this protein is unknown. Alternatively spliced transcript variants encoding different isoforms exist. [provided by RefSeq, Jul 2008]

EPS8L3 links:

GSTM5 (HGNC:4637): (glutathione S-transferase mu 5) Cytosolic and membrane-bound forms of glutathione S-transferase are encoded by two distinct supergene families. At present, eight distinct classes of the soluble cytoplasmic mammalian glutathione S-transferases have been identified: alpha, kappa, mu, omega, pi, sigma, theta and zeta. This gene encodes a glutathione S-transferase that belongs to the mu class. The mu class of enzymes functions in the detoxification of electrophilic compounds, including carcinogens, therapeutic drugs, environmental toxins and products of oxidative stress, by conjugation with glutathione. The genes encoding the mu class of enzymes are organized in a gene cluster on chromosome 1p13.3 and are known to be highly polymorphic. These genetic variations can change an individual's susceptibility to carcinogens and toxins as well as affect the toxicity and efficacy of certain drugs. Diversification of these genes has occurred in regions encoding substrate-binding domains, as well as in tissue expression patterns, to accommodate an increasing number of foreign compounds. [provided by RefSeq, Jul 2008]

GSTM5 links:

ENSG00000241720 (HGNC:):

ENSG00000241720 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002686292).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.364 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPS8L3	NM_133181.4 link	c.1066C>T	p.Pro356Ser	missense_variant	Exon 12 of 19	ENST00000361965.9	NP_573444.2	Q8TE67-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPS8L3	ENST00000361965.9 link	c.1066C>T	p.Pro356Ser	missense_variant	Exon 12 of 19	1	NM_133181.4	ENSP00000355255.4		Q8TE67-1

Frequencies

GnomAD3 genomes

AF:

0.151

AC:

23009

AN:

152014

Hom.:

3230

Cov.:

show subpopulations

Gnomad AFR

AF:

0.369

Gnomad AMI

AF:

0.133

Gnomad AMR

AF:

0.124

Gnomad ASJ

AF:

0.0547

Gnomad EAS

AF:

0.00906

Gnomad SAS

AF:

0.0756

Gnomad FIN

AF:

0.0642

Gnomad MID

AF:

0.114

Gnomad NFE

AF:

0.0610

Gnomad OTH

AF:

0.129

GnomAD3 exomes

AF:

0.0936

AC:

23531

AN:

251378

Hom.:

2063

AF XY:

0.0858

AC XY:

11650

AN XY:

135854

show subpopulations

Gnomad AFR exome

AF:

0.377

Gnomad AMR exome

AF:

0.161

Gnomad ASJ exome

AF:

0.0649

Gnomad EAS exome

AF:

0.00179

Gnomad SAS exome

AF:

0.0786

Gnomad FIN exome

AF:

0.0605

Gnomad NFE exome

AF:

0.0614

Gnomad OTH exome

AF:

0.0755

GnomAD4 exome

AF:

0.0709

AC:

103587

AN:

1461802

Hom.:

5753

Cov.:

AF XY:

0.0699

AC XY:

50842

AN XY:

727202

show subpopulations

Gnomad4 AFR exome

AF:

0.379

Gnomad4 AMR exome

AF:

0.155

Gnomad4 ASJ exome

AF:

0.0636

Gnomad4 EAS exome

AF:

0.0221

Gnomad4 SAS exome

AF:

0.0805

Gnomad4 FIN exome

AF:

0.0595

Gnomad4 NFE exome

AF:

0.0593

Gnomad4 OTH exome

AF:

0.0787

GnomAD4 genome

AF:

0.151

AC:

23035

AN:

152132

Hom.:

3233

Cov.:

AF XY:

0.149

AC XY:

11065

AN XY:

74400

show subpopulations

Gnomad4 AFR

AF:

0.369

Gnomad4 AMR

AF:

0.124

Gnomad4 ASJ

AF:

0.0547

Gnomad4 EAS

AF:

0.00889

Gnomad4 SAS

AF:

0.0759

Gnomad4 FIN

AF:

0.0642

Gnomad4 NFE

AF:

0.0610

Gnomad4 OTH

AF:

0.128

Alfa

AF:

0.0762

Hom.:

1914

Bravo

AF:

0.165

TwinsUK

AF:

0.0599

AC:

222

ALSPAC

AF:

0.0576

AC:

222

ESP6500AA

AF:

0.365

AC:

1606

ESP6500EA

AF:

0.0628

AC:

540

ExAC

AF:

0.0980

AC:

11898

Asia WGS

AF:

0.0530

AC:

185

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.51

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.036

.;.;T

Eigen

Benign

-0.69

Eigen_PC

Benign

-0.62

FATHMM_MKL

Benign

0.047

LIST_S2

Benign

0.70

T;T;T

MetaRNN

Benign

0.0027

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.1

M;.;M

PrimateAI

Benign

0.31

PROVEAN

Pathogenic

-5.9

D;D;D

REVEL

Benign

0.091

Sift

Benign

0.067

T;T;T

Sift4G

Benign

0.29

T;T;T

Polyphen

0.42

B;P;B

Vest4

0.14

MPC

0.11

ClinPred

0.015

GERP RS

4.5

Varity_R

0.15

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over