Genetic Variant EPS8:p.Asp761Glu (chr12-15623230-A-T) – 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.2283T>A(p.Asp761Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,256 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. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D761N) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

EPS8
NM_004447.6 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.221

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: Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen, PanelApp Australia
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=0.075606614).

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.2283T>A	p.Asp761Glu	missense	Exon 20 of 21	NP_004438.3
EPS8	NM_001413831.1		c.2319T>A	p.Asp773Glu	missense	Exon 21 of 22	NP_001400760.1
EPS8	NM_001413832.1		c.2283T>A	p.Asp761Glu	missense	Exon 21 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.2283T>A	p.Asp761Glu	missense	Exon 20 of 21	ENSP00000281172.5	Q12929-1
EPS8	ENST00000543468.5	TSL:1	n.*1543T>A		non_coding_transcript_exon	Exon 19 of 20	ENSP00000445985.1	F5H0R8
EPS8	ENST00000543468.5	TSL:1	n.*1543T>A		3_prime_UTR	Exon 19 of 20	ENSP00000445985.1	F5H0R8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461256

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726948

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33454

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26112

East Asian (EAS)

AF:

0.00

AC:

AN:

39672

South Asian (SAS)

AF:

0.00

AC:

AN:

86202

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1111550

Other (OTH)

AF:

0.00

AC:

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.458

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

0.072

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.61

CADD

Benign

4.8

(source)

DANN

Benign

0.85

DEOGEN2

Benign

0.11

Eigen

Benign

-0.65

Eigen_PC

Benign

-0.44

FATHMM_MKL

Benign

0.75

LIST_S2

Benign

0.53

M_CAP

Benign

0.0052

MetaRNN

Benign

0.076

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.33

PhyloP100

0.22

PrimateAI

Uncertain

0.56

PROVEAN

Benign

0.15

REVEL

Benign

0.16

Sift

Benign

0.99

Sift4G

Benign

0.52

Polyphen

0.0

Vest4

0.22

MutPred

0.18

Gain of ubiquitination at K760 (P = 0.0945)

MVP

0.31

MPC

0.11

ClinPred

0.16

GERP RS

1.9

Varity_R

0.042

gMVP

0.24

Mutation Taster

=94/6

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