Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_004447.6(EPS8):c.1482T>C(p.Ser494Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00576 in 1,613,874 control chromosomes in the GnomAD database, including 52 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0057 ( 14 hom., cov: 33)

Exomes 𝑓: 0.0058 ( 38 hom. )

Consequence

EPS8
NM_004447.6 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 1.17

Publications

1 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 12-15647213-A-G is Benign according to our data. Variant chr12-15647213-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 517547.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.17 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00574 (874/152358) while in subpopulation NFE AF = 0.00742 (505/68032). AF 95% confidence interval is 0.00689. There are 14 homozygotes in GnomAd4. There are 436 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 14 AR gene

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.1482T>C	p.Ser494Ser	synonymous	Exon 15 of 21	NP_004438.3
EPS8	NM_001413831.1		c.1482T>C	p.Ser494Ser	synonymous	Exon 15 of 22	NP_001400760.1
EPS8	NM_001413832.1		c.1482T>C	p.Ser494Ser	synonymous	Exon 16 of 22	NP_001400761.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
EPS8	ENST00000281172.10	TSL:1 MANE Select	c.1482T>C	p.Ser494Ser	synonymous	Exon 15 of 21	ENSP00000281172.5
EPS8	ENST00000543468.5	TSL:1	n.*742T>C		non_coding_transcript_exon	Exon 14 of 20	ENSP00000445985.1
EPS8	ENST00000543468.5	TSL:1	n.*742T>C		3_prime_UTR	Exon 14 of 20	ENSP00000445985.1

Frequencies

GnomAD3 genomes

AF:

0.00575

AC:

875

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00133

Gnomad AMI

AF:

0.151

Gnomad AMR

AF:

0.00321

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0111

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00744

Gnomad OTH

AF:

0.00334

GnomAD2 exomes

AF:

0.00509

AC:

1278

AN:

251206

AF XY:

0.00483

show subpopulations

Gnomad AFR exome

AF:

0.000923

Gnomad AMR exome

AF:

0.00188

Gnomad ASJ exome

AF:

0.000397

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0103

Gnomad NFE exome

AF:

0.00829

Gnomad OTH exome

AF:

0.00457

GnomAD4 exome

AF:

0.00576

AC:

8417

AN:

1461516

Hom.:

Cov.:

AF XY:

0.00549

AC XY:

3990

AN XY:

727050

show subpopulations

African (AFR)

AF:

0.00102

AC:

AN:

33468

American (AMR)

AF:

0.00190

AC:

AN:

44696

Ashkenazi Jewish (ASJ)

AF:

0.000536

AC:

AN:

26128

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39692

South Asian (SAS)

AF:

0.0000464

AC:

AN:

86222

European-Finnish (FIN)

AF:

0.0104

AC:

555

AN:

53414

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00670

AC:

7447

AN:

1111756

Other (OTH)

AF:

0.00457

AC:

276

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

382

764

1146

1528

1910

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

272

544

816

1088

1360

<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:

0.00574

AC:

874

AN:

152358

Hom.:

Cov.:

AF XY:

0.00585

AC XY:

436

AN XY:

74500

show subpopulations

African (AFR)

AF:

0.00132

AC:

AN:

41592

American (AMR)

AF:

0.00320

AC:

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.000207

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0111

AC:

118

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00742

AC:

505

AN:

68032

Other (OTH)

AF:

0.00331

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

133

178

222

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00557

Hom.:

Bravo

AF:

0.00514

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00529

EpiControl

AF:

0.00658

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

EPS8-related disorder (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

1.6

(source)

DANN

Benign

0.51

PhyloP100

1.2

Mutation Taster

=100/0

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

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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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over