rs75560906

chr12-15647213-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_004447.6(EPS8):c.1482T>C(p.Ser494=) 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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.17

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 -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 [Likely_benign]. Clinvar id 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 male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPS8	NM_004447.6	c.1482T>C	p.Ser494=	synonymous_variant	15/21	ENST00000281172.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPS8	ENST00000281172.10	c.1482T>C	p.Ser494=	synonymous_variant	15/21	1	NM_004447.6	P1

Frequencies

GnomAD3 genomes AF: 0.00575 AC: 875 AN: 152240 Hom.: 14 Cov.: 33

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

GnomAD3 exomes AF: 0.00509 AC: 1278 AN: 251206 Hom.: 12 AF XY: 0.00483 AC XY: 655 AN XY: 135748

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 SAS exome AF: 0.0000654

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.: 38 Cov.: 30 AF XY: 0.00549 AC XY: 3990 AN XY: 727050

Gnomad4 AFR exome AF: 0.00102

Gnomad4 AMR exome AF: 0.00190

Gnomad4 ASJ exome AF: 0.000536

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.0104

Gnomad4 NFE exome AF: 0.00670

Gnomad4 OTH exome AF: 0.00457

GnomAD4 genome AF: 0.00574 AC: 874 AN: 152358 Hom.: 14 Cov.: 33 AF XY: 0.00585 AC XY: 436 AN XY: 74500

Gnomad4 AFR AF: 0.00132

Gnomad4 AMR AF: 0.00320

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0111

Gnomad4 NFE AF: 0.00742

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00557 Hom.: 0

Bravo AF: 0.00514

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00529

EpiControl AF: 0.00658

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 18, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2022	EPS8: BP4, BP7, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 05, 2018	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 specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 23, 2017

p.Ser494Ser in exon 15 of EPS8: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue, is not located withi n the splice consensus sequence, and has been identified in 1.12% (74/6614) of F innish chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadi nstitute.org; dbSNP rs75560906). -

EPS8-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 09, 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	-0.83
Cadd	Benign	1.6
Dann	Benign	0.51

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

Other links and lift over

dbSNP: rs75560906; hg19: chr12-15800147; COSMIC: COSV55529652;