Genetic Variant EPS8:c.2226-6_2226-3delTTTT (chr12-15623289-TAAAA-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004447.6(EPS8):c.2226-6_2226-3delTTTT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000501 in 1,197,034 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000050 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

EPS8
NM_004447.6 splice_region, intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.181

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

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.2226-6_2226-3delTTTT	splice_region intron	N/A	NP_004438.3
EPS8	NM_001413831.1		c.2262-6_2262-3delTTTT	splice_region intron	N/A	NP_001400760.1
EPS8	NM_001413832.1		c.2226-6_2226-3delTTTT	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.2226-6_2226-3delTTTT	splice_region intron	N/A	ENSP00000281172.5
EPS8	ENST00000543468.5	TSL:1	n.1486-6_1486-3delTTTT	splice_region intron	N/A	ENSP00000445985.1
EPS8	ENST00000642939.1		c.2277-6_2277-3delTTTT	splice_region intron	N/A	ENSP00000495312.1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

136636

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000501

AC:

AN:

1197034

Hom.:

AF XY:

0.00000501

AC XY:

AN XY:

598450

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:

27300

American (AMR)

AF:

0.00

AC:

AN:

27756

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21020

East Asian (EAS)

AF:

0.00

AC:

AN:

34940

South Asian (SAS)

AF:

0.0000144

AC:

AN:

69462

European-Finnish (FIN)

AF:

0.0000231

AC:

AN:

43240

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4688

European-Non Finnish (NFE)

AF:

0.00000436

AC:

AN:

918256

Other (OTH)

AF:

0.00

AC:

AN:

50372

⚠️ 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: 0.225

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

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

136636

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

66042

African (AFR)

AF:

0.00

AC:

AN:

38168

American (AMR)

AF:

0.00

AC:

AN:

13472

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3222

East Asian (EAS)

AF:

0.00

AC:

AN:

4808

South Asian (SAS)

AF:

0.00

AC:

AN:

4204

European-Finnish (FIN)

AF:

0.00

AC:

AN:

7674

Middle Eastern (MID)

AF:

0.00

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

62070

Other (OTH)

AF:

0.00

AC:

AN:

1868

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.18

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over