rs150904526

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS1

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. 13/22 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:6

Conservation

PhyloP100: 5.91

Publications

3 publications found

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 Gene-Disease associations (from GenCC):

autosomal recessive nonsyndromic hearing loss 102
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

EPS8 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004447.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EPS8	NM_004447.6	MANE Select	c.2177C>T	p.Thr726Ile	missense	Exon 19 of 21	NP_004438.3
EPS8	NM_001413831.1		c.2213C>T	p.Thr738Ile	missense	Exon 20 of 22	NP_001400760.1
EPS8	NM_001413832.1		c.2177C>T	p.Thr726Ile	missense	Exon 20 of 22	NP_001400761.1	Q12929-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EPS8	ENST00000281172.10	TSL:1 MANE Select	c.2177C>T	p.Thr726Ile	missense	Exon 19 of 21	ENSP00000281172.5	Q12929-1
EPS8	ENST00000543468.5	TSL:1	n.*1437C>T		non_coding_transcript_exon	Exon 18 of 20	ENSP00000445985.1	F5H0R8
EPS8	ENST00000543468.5	TSL:1	n.*1437C>T		3_prime_UTR	Exon 18 of 20	ENSP00000445985.1	F5H0R8

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

GnomAD2 exomes

AF:

0.000382

AC:

AN:

251084

AF XY:

0.000383

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 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

African (AFR)

AF:

0.000149

AC:

AN:

33468

American (AMR)

AF:

0.0000894

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39688

South Asian (SAS)

AF:

0.00

AC:

AN:

86234

European-Finnish (FIN)

AF:

0.0000749

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.000533

AC:

AN:

5626

European-Non Finnish (NFE)

AF:

0.000928

AC:

1032

AN:

1111906

Other (OTH)

AF:

0.000265

AC:

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.454

Heterozygous variant carriers

100

149

199

249

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

138

184

230

<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:

0.000400

AC:

AN:

152314

Hom.:

Cov.:

AF XY:

0.000322

AC XY:

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.0000962

AC:

AN:

41568

American (AMR)

AF:

0.0000654

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0000941

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000809

AC:

AN:

68024

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.000660

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

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Autosomal recessive nonsyndromic hearing loss 102 (1)

Inborn genetic diseases (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.39

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.78

Eigen

Benign

0.035

Eigen_PC

Benign

0.12

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.66

M_CAP

Benign

0.010

MetaRNN

Benign

0.13

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.7

PhyloP100

5.9

PrimateAI

Benign

0.48

PROVEAN

Uncertain

-2.5

REVEL

Benign

0.15

Sift

Benign

0.059

Sift4G

Uncertain

0.048

Polyphen

0.11

Vest4

0.28

MVP

0.27

MPC

0.13

ClinPred

0.034

GERP RS

5.4

Varity_R

0.098

gMVP

0.66

Mutation Taster

=74/26

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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