Genetic Variant EPS8:c.*10_*13delTTGT (chr12-15621303-TACAA-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2BP6_ModerateBS1

The NM_004447.6(EPS8):c.*10_*13delTTGT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000443 in 1,422,896 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000035 ( 0 hom. )

Consequence

EPS8
NM_004447.6 3_prime_UTR

Scores

Not classified

Clinical Significance

Likely benign criteria provided, single submitter B:2

Conservation

PhyloP100: 1.37

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 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP6

Variant 12-15621303-TACAA-T is Benign according to our data. Variant chr12-15621303-TACAA-T is described in ClinVar as [Likely_benign]. Clinvar id is 1254677.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000118 (18/152118) while in subpopulation AFR AF = 0.000193 (8/41432). AF 95% confidence interval is 0.0000957. There are 0 homozygotes in GnomAd4. There are 11 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPS8	NM_004447.6 link	c.10_13delTTGT		3_prime_UTR_variant	Exon 21 of 21	ENST00000281172.10	NP_004438.3	Q12929-1B4E3T6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPS8	ENST00000281172 link	c.10_13delTTGT		3_prime_UTR_variant	Exon 21 of 21	1	NM_004447.6	ENSP00000281172.5		Q12929-1

Frequencies

GnomAD3 genomes

AF:

0.000118

AC:

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.000103

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.0000331

AC:

AN:

211756

AF XY:

0.0000260

show subpopulations

Gnomad AFR exome

AF:

0.000149

Gnomad AMR exome

AF:

0.0000409

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000491

Gnomad NFE exome

AF:

0.0000198

Gnomad OTH exome

AF:

0.000205

GnomAD4 exome

AF:

0.0000354

AC:

AN:

1270778

Hom.:

AF XY:

0.0000281

AC XY:

AN XY:

639746

show subpopulations

Gnomad4 AFR exome

AF:

0.000145

AC:

AN:

27596

Gnomad4 AMR exome

AF:

0.0000861

AC:

AN:

34850

Gnomad4 ASJ exome

AF:

0.00

AC:

AN:

24204

Gnomad4 EAS exome

AF:

0.00

AC:

AN:

36112

Gnomad4 SAS exome

AF:

0.00

AC:

AN:

74848

Gnomad4 FIN exome

AF:

0.0000192

AC:

AN:

52180

Gnomad4 NFE exome

AF:

0.0000364

AC:

AN:

961862

Gnomad4 Remaining exome

AF:

0.0000372

AC:

AN:

53736

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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

AF:

0.000118

AC:

AN:

152118

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74320

show subpopulations

Gnomad4 AFR

AF:

0.000193

AC:

0.000193087

AN:

0.000193087

Gnomad4 AMR

AF:

0.000131

AC:

0.000131062

AN:

0.000131062

Gnomad4 ASJ

AF:

0.00

AC:

AN:

Gnomad4 EAS

AF:

0.00

AC:

AN:

Gnomad4 SAS

AF:

0.00

AC:

AN:

Gnomad4 FIN

AF:

0.00

AC:

AN:

Gnomad4 NFE

AF:

0.000103

AC:

0.000102923

AN:

0.000102923

Gnomad4 OTH

AF:

0.000479

AC:

0.000478927

AN:

0.000478927

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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.:

Bravo

AF:

0.000110

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

EPS8-related disorder

Benign:1

Nov 21, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

Aug 24, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Mutation Taster

=100/0

polymorphism

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over