NM_004447.6:c.2226-3delT

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP6_Very_Strong

The NM_004447.6(EPS8):c.2226-3delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00336 in 136,300 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0034 ( 0 hom., cov: 31)

Exomes 𝑓: 0.26 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

EPS8
NM_004447.6 splice_region, intron

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.00600

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 -8 ACMG points.

BP6

Variant 12-15623289-TA-T is Benign according to our data. Variant chr12-15623289-TA-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 666690.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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	Effect	Exon Rank	Protein
EPS8	NM_004447.6	MANE Select	c.2226-3delT	splice_region intron	N/A	NP_004438.3
EPS8	NM_001413831.1		c.2262-3delT	splice_region intron	N/A	NP_001400760.1
EPS8	NM_001413832.1		c.2226-3delT	splice_region intron	N/A	NP_001400761.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
EPS8	ENST00000281172.10	TSL:1 MANE Select	c.2226-3delT	splice_region intron	N/A	ENSP00000281172.5
EPS8	ENST00000543468.5	TSL:1	n.*1486-3delT	splice_region intron	N/A	ENSP00000445985.1
EPS8	ENST00000642939.1		c.2277-3delT	splice_region intron	N/A	ENSP00000495312.1

Frequencies

GnomAD3 genomes

AF:

0.00336

AC:

458

AN:

136278

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00165

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00290

Gnomad ASJ

AF:

0.00342

Gnomad EAS

AF:

0.00187

Gnomad SAS

AF:

0.000952

Gnomad FIN

AF:

0.0148

Gnomad MID

AF:

0.00347

Gnomad NFE

AF:

0.00340

Gnomad OTH

AF:

0.00430

GnomAD2 exomes

AF:

0.351

AC:

39404

AN:

112150

AF XY:

0.365

show subpopulations

Gnomad AFR exome

AF:

0.147

Gnomad AMR exome

AF:

0.376

Gnomad ASJ exome

AF:

0.401

Gnomad EAS exome

AF:

0.359

Gnomad FIN exome

AF:

0.334

Gnomad NFE exome

AF:

0.368

Gnomad OTH exome

AF:

0.358

GnomAD4 exome

Data not reliable, filtered out with message: InbreedingCoeff

AF:

0.258

AC:

238488

AN:

925642

Hom.:

Cov.:

AF XY:

0.263

AC XY:

121339

AN XY:

461256

show subpopulations

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

African (AFR)

AF:

0.119

AC:

2874

AN:

24252

American (AMR)

AF:

0.297

AC:

6536

AN:

22034

Ashkenazi Jewish (ASJ)

AF:

0.296

AC:

4845

AN:

16372

East Asian (EAS)

AF:

0.296

AC:

7363

AN:

24890

South Asian (SAS)

AF:

0.296

AC:

17073

AN:

57748

European-Finnish (FIN)

AF:

0.289

AC:

9366

AN:

32442

Middle Eastern (MID)

AF:

0.197

AC:

738

AN:

3748

European-Non Finnish (NFE)

AF:

0.255

AC:

179590

AN:

705148

Other (OTH)

AF:

0.259

AC:

10103

AN:

39008

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.271

Heterozygous variant carriers

24025

48050

72075

96100

120125

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

6208

12416

18624

24832

31040

<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:

0.00336

AC:

458

AN:

136300

Hom.:

Cov.:

AF XY:

0.00408

AC XY:

269

AN XY:

65870

show subpopulations

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

African (AFR)

AF:

0.00165

AC:

AN:

38222

American (AMR)

AF:

0.00283

AC:

AN:

13450

Ashkenazi Jewish (ASJ)

AF:

0.00342

AC:

AN:

3212

East Asian (EAS)

AF:

0.00188

AC:

AN:

4782

South Asian (SAS)

AF:

0.000955

AC:

AN:

4188

European-Finnish (FIN)

AF:

0.0148

AC:

113

AN:

7622

Middle Eastern (MID)

AF:

0.00373

AC:

AN:

268

European-Non Finnish (NFE)

AF:

0.00340

AC:

210

AN:

61822

Other (OTH)

AF:

0.00481

AC:

AN:

1872

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.315

Heterozygous variant carriers

109

145

181

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:

0.00

Hom.:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

May 07, 2018

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

c.2226-3delT in intron 19 of EPS8: This variant is likely benign because it is n ot predicted to impact splicing. Furthermore, this variant is a deletion of 1 of 13 consecutive Ts in the intron, which is a repetivie region without known fu nction. ACMG/AMP Criteria applied: BP3, BP4.

not provided

Benign:1

Nov 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.0060

Mutation Taster

=95/5

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over