dbSNP rs3818562: EPS8L3:p.His293Tyr (chr1-109757819-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.877C>T(p.His293Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.484 in 1,613,184 control chromosomes in the GnomAD database, including 194,190 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict 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 0.42 ( 14715 hom., cov: 32)

Exomes 𝑓: 0.49 ( 179475 hom. )

Consequence

EPS8L3
NM_133181.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.32

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=7.517285E-6).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.751 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPS8L3	NM_133181.4 link	c.877C>T	p.His293Tyr	missense_variant	Exon 10 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.877C>T	p.His293Tyr	missense_variant	Exon 10 of 19	1	NM_133181.4	ENSP00000355255.4		Q8TE67-1

Frequencies

GnomAD3 genomes

AF:

0.418

AC:

63486

AN:

151970

Hom.:

14717

Cov.:

show subpopulations

Gnomad AFR

AF:

0.226

Gnomad AMI

AF:

0.456

Gnomad AMR

AF:

0.416

Gnomad ASJ

AF:

0.506

Gnomad EAS

AF:

0.773

Gnomad SAS

AF:

0.573

Gnomad FIN

AF:

0.407

Gnomad MID

AF:

0.402

Gnomad NFE

AF:

0.494

Gnomad OTH

AF:

0.421

GnomAD3 exomes

AF:

0.486

AC:

121648

AN:

250458

Hom.:

31346

AF XY:

0.494

AC XY:

66824

AN XY:

135326

show subpopulations

Gnomad AFR exome

AF:

0.213

Gnomad AMR exome

AF:

0.427

Gnomad ASJ exome

AF:

0.496

Gnomad EAS exome

AF:

0.777

Gnomad SAS exome

AF:

0.575

Gnomad FIN exome

AF:

0.403

Gnomad NFE exome

AF:

0.488

Gnomad OTH exome

AF:

0.463

GnomAD4 exome

AF:

0.491

AC:

716670

AN:

1461096

Hom.:

179475

Cov.:

AF XY:

0.494

AC XY:

359115

AN XY:

726912

show subpopulations

Gnomad4 AFR exome

AF:

0.211

Gnomad4 AMR exome

AF:

0.424

Gnomad4 ASJ exome

AF:

0.500

Gnomad4 EAS exome

AF:

0.751

Gnomad4 SAS exome

AF:

0.567

Gnomad4 FIN exome

AF:

0.410

Gnomad4 NFE exome

AF:

0.491

Gnomad4 OTH exome

AF:

0.486

GnomAD4 genome

AF:

0.418

AC:

63506

AN:

152088

Hom.:

14715

Cov.:

AF XY:

0.416

AC XY:

30917

AN XY:

74332

show subpopulations

Gnomad4 AFR

AF:

0.226

Gnomad4 AMR

AF:

0.415

Gnomad4 ASJ

AF:

0.506

Gnomad4 EAS

AF:

0.771

Gnomad4 SAS

AF:

0.573

Gnomad4 FIN

AF:

0.407

Gnomad4 NFE

AF:

0.494

Gnomad4 OTH

AF:

0.425

Alfa

AF:

0.483

Hom.:

45136

Bravo

AF:

0.408

TwinsUK

AF:

0.486

AC:

1803

ALSPAC

AF:

0.493

AC:

1901

ESP6500AA

AF:

0.232

AC:

1023

ESP6500EA

AF:

0.491

AC:

4224

ExAC

AF:

0.484

AC:

58775

Asia WGS

AF:

0.606

AC:

2107

AN:

3478

EpiCase

AF:

0.486

EpiControl

AF:

0.476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.040

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.51

CADD

Benign

DANN

Benign

0.80

DEOGEN2

Benign

0.0035

.;.;T

Eigen

Benign

-0.98

Eigen_PC

Benign

-0.70

FATHMM_MKL

Benign

0.024

LIST_S2

Benign

0.087

T;T;T

MetaRNN

Benign

0.0000075

T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-1.2

N;.;N

PrimateAI

Benign

0.41

PROVEAN

Benign

1.5

N;N;N

REVEL

Benign

0.030

Sift

Benign

1.0

T;T;T

Sift4G

Benign

1.0

T;T;T

Polyphen

0.0

B;B;B

Vest4

0.13

MPC

0.099

ClinPred

0.0055

GERP RS

2.7

Varity_R

0.071

gMVP

0.23

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over