rs73315036

chr12-15669381-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004447.6(EPS8):c.516+6A>G variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0103 in 1,592,022 control chromosomes in the GnomAD database, including 1,196 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.049 (590 hom., cov: 33)
  • Exomes 𝑓: 0.0062 (606 hom.)
• Consequence: EPS8 NM_004447.6 splice_donor_region, intron
• Scores: Splicing: ADA: 0.00004658
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.02

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 12-15669381-T-C is Benign according to our data. Variant chr12-15669381-T-C is described in ClinVar as [Benign]. Clinvar id is 508706.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.161 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPS8	NM_004447.6	c.516+6A>G		splice_donor_region_variant, intron_variant		ENST00000281172.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPS8	ENST00000281172.10	c.516+6A>G		splice_donor_region_variant, intron_variant		1	NM_004447.6	P1

Frequencies

GnomAD3 genomes AF: 0.0493 AC: 7505 AN: 152168 Hom.: 590 Cov.: 33

Gnomad AFR AF: 0.165

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0282

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00172

Gnomad OTH AF: 0.0493

GnomAD3 exomes AF: 0.0150 AC: 3451 AN: 229342 Hom.: 246 AF XY: 0.0112 AC XY: 1392 AN XY: 123914

Gnomad AFR exome AF: 0.173

Gnomad AMR exome AF: 0.0135

Gnomad ASJ exome AF: 0.00408

Gnomad EAS exome AF: 0.0000581

Gnomad SAS exome AF: 0.000503

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00204

Gnomad OTH exome AF: 0.0107

GnomAD4 exome AF: 0.00616 AC: 8868 AN: 1439736 Hom.: 606 Cov.: 31 AF XY: 0.00558 AC XY: 3988 AN XY: 715144

Gnomad4 AFR exome AF: 0.177

Gnomad4 AMR exome AF: 0.0152

Gnomad4 ASJ exome AF: 0.00402

Gnomad4 EAS exome AF: 0.000228

Gnomad4 SAS exome AF: 0.000391

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.00139

Gnomad4 OTH exome AF: 0.0135

GnomAD4 genome AF: 0.0494 AC: 7520 AN: 152286 Hom.: 590 Cov.: 33 AF XY: 0.0475 AC XY: 3539 AN XY: 74464

Gnomad4 AFR AF: 0.165

Gnomad4 AMR AF: 0.0281

Gnomad4 ASJ AF: 0.00519

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00172

Gnomad4 OTH AF: 0.0488

Alfa AF: 0.0227 Hom.: 129

Bravo AF: 0.0573

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 23, 2017	c.516+6A>G in intron 6 of EPS8: This variant is not expected to have clinical si gnificance because it has been identified in 17.58% (1791/10186) of African chro mosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.or g; dbSNP rs73315036). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 05, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 15, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -

EPS8-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 01, 2019

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

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	10
Dann	Benign	0.69

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000047
dbscSNV1_RF	Benign	0.0020
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

Other links and lift over

dbSNP: rs73315036; hg19: chr12-15822315; COSMIC: COSV55533745; COSMIC: COSV55533745;