chr1-109757819-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

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

Publications

45 publications found

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 was made for transcript

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_133181.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EPS8L3	NM_133181.4	MANE Select	c.877C>T	p.His293Tyr	missense	Exon 10 of 19	NP_573444.2
EPS8L3	NM_139053.3		c.880C>T	p.His294Tyr	missense	Exon 10 of 19	NP_620641.1	Q8TE67-3
EPS8L3	NM_024526.4		c.877C>T	p.His293Tyr	missense	Exon 10 of 19	NP_078802.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EPS8L3	ENST00000361965.9	TSL:1 MANE Select	c.877C>T	p.His293Tyr	missense	Exon 10 of 19	ENSP00000355255.4	Q8TE67-1
EPS8L3	ENST00000369805.7	TSL:1	c.880C>T	p.His294Tyr	missense	Exon 10 of 19	ENSP00000358820.3	Q8TE67-3
EPS8L3	ENST00000361852.8	TSL:1	c.877C>T	p.His293Tyr	missense	Exon 10 of 19	ENSP00000354551.4	Q8TE67-2

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

GnomAD2 exomes

AF:

0.486

AC:

121648

AN:

250458

AF XY:

0.494

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 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

African (AFR)

AF:

0.211

AC:

7064

AN:

33472

American (AMR)

AF:

0.424

AC:

18959

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.500

AC:

13074

AN:

26134

East Asian (EAS)

AF:

0.751

AC:

29796

AN:

39698

South Asian (SAS)

AF:

0.567

AC:

48922

AN:

86250

European-Finnish (FIN)

AF:

0.410

AC:

21912

AN:

53402

Middle Eastern (MID)

AF:

0.426

AC:

2458

AN:

5766

European-Non Finnish (NFE)

AF:

0.491

AC:

545150

AN:

1111284

Other (OTH)

AF:

0.486

AC:

29335

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

20752

41504

62255

83007

103759

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

15940

31880

47820

63760

79700

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.418

AC:

63506

AN:

152088

Hom.:

14715

Cov.:

AF XY:

0.416

AC XY:

30917

AN XY:

74332

show subpopulations

African (AFR)

AF:

0.226

AC:

9374

AN:

41526

American (AMR)

AF:

0.415

AC:

6345

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.506

AC:

1756

AN:

3472

East Asian (EAS)

AF:

0.771

AC:

3982

AN:

5162

South Asian (SAS)

AF:

0.573

AC:

2761

AN:

4822

European-Finnish (FIN)

AF:

0.407

AC:

4297

AN:

10558

Middle Eastern (MID)

AF:

0.418

AC:

123

AN:

294

European-Non Finnish (NFE)

AF:

0.494

AC:

33556

AN:

67942

Other (OTH)

AF:

0.425

AC:

896

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1777

3554

5331

7108

8885

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

608

1216

1824

2432

3040

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.476

Hom.:

80867

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 v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.040

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Benign

0.80

DEOGEN2

Benign

0.0035

Eigen

Benign

-0.98

Eigen_PC

Benign

-0.70

FATHMM_MKL

Benign

0.024

LIST_S2

Benign

0.087

MetaRNN

Benign

0.0000075

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-1.2

PhyloP100

1.3

PrimateAI

Benign

0.41

PROVEAN

Benign

1.5

REVEL

Benign

0.030

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.13

MPC

0.099

ClinPred

0.0055

GERP RS

2.7

Varity_R

0.071

gMVP

0.23

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over