Genetic Variant EPS8:p.Gln30Glu (chr12-15681274-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004447.6(EPS8):c.88C>G(p.Gln30Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00000143 in 1,398,758 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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: not found (cov: 31)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

EPS8
NM_004447.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.80

Publications

0 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: ClinGen, PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae)
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

EPS8 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.17340702).

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
EPS8	NM_004447.6	MANE Select	c.88C>G	p.Gln30Glu	missense	Exon 3 of 21	NP_004438.3
EPS8	NM_001413831.1		c.88C>G	p.Gln30Glu	missense	Exon 3 of 22	NP_001400760.1
EPS8	NM_001413832.1		c.88C>G	p.Gln30Glu	missense	Exon 4 of 22	NP_001400761.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
EPS8	ENST00000281172.10	TSL:1 MANE Select	c.88C>G	p.Gln30Glu	missense	Exon 3 of 21	ENSP00000281172.5
EPS8	ENST00000543468.5	TSL:1	n.88C>G		non_coding_transcript_exon	Exon 3 of 20	ENSP00000445985.1
EPS8	ENST00000642939.1		c.88C>G	p.Gln30Glu	missense	Exon 4 of 23	ENSP00000495312.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000143

AC:

AN:

1398758

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

696510

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

31316

American (AMR)

AF:

0.00

AC:

AN:

41134

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24902

East Asian (EAS)

AF:

0.00

AC:

AN:

37390

South Asian (SAS)

AF:

0.00

AC:

AN:

77786

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51590

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5140

European-Non Finnish (NFE)

AF:

9.33e-7

AC:

AN:

1071982

Other (OTH)

AF:

0.0000174

AC:

AN:

57518

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0385499), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.075

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

DANN

Benign

0.87

DEOGEN2

Benign

0.21

Eigen

Benign

0.030

Eigen_PC

Benign

0.18

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.82

M_CAP

Benign

0.0079

MetaRNN

Benign

0.17

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.7

PhyloP100

4.8

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.45

REVEL

Benign

0.11

Sift

Benign

0.19

Sift4G

Benign

0.67

Polyphen

0.24

Vest4

0.42

MutPred

0.094

Gain of phosphorylation at S29 (P = 0.1094)

MVP

0.57

MPC

0.16

ClinPred

0.76

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.14

gMVP

0.26

Mutation Taster

=89/11

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over