NM_004447.6:c.2352G>A

Variant names:

• chr12-15623161-C-T
• rs1126786
• NM_004447.6:c.2352G>A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_004447.6(EPS8):​c.2352G>A​(p.Leu784Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0487 in 1,604,462 control chromosomes in the GnomAD database, including 10,231 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (5081 hom., cov: 32)
  • Exomes 𝑓: 0.038 (5150 hom.)
• Consequence: EPS8 NM_004447.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.489

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 12-15623161-C-T is Benign according to our data. Variant chr12-15623161-C-T is described in ClinVar as [Benign]. Clinvar id is 508137.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.489 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.48 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPS8	NM_004447.6	c.2352G>A	p.Leu784Leu	synonymous_variant	Exon 20 of 21	ENST00000281172.10	NP_004438.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EPS8	ENST00000281172.10	c.2352G>A	p.Leu784Leu	synonymous_variant	Exon 20 of 21	1	NM_004447.6	ENSP00000281172.5

Frequencies

GnomAD3 genomes AF: 0.154 AC: 23361 AN: 151970 Hom.: 5072 Cov.: 32

Gnomad AFR AF: 0.485

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.0655

Gnomad ASJ AF: 0.0196

Gnomad EAS AF: 0.0415

Gnomad SAS AF: 0.0459

Gnomad FIN AF: 0.00245

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.0222

Gnomad OTH AF: 0.115

GnomAD3 exomes AF: 0.0578 AC: 13963 AN: 241568 Hom.: 2125 AF XY: 0.0493 AC XY: 6430 AN XY: 130322

Gnomad AFR exome AF: 0.495

Gnomad AMR exome AF: 0.0316

Gnomad ASJ exome AF: 0.0244

Gnomad EAS exome AF: 0.0433

Gnomad SAS exome AF: 0.0440

Gnomad FIN exome AF: 0.00397

Gnomad NFE exome AF: 0.0223

Gnomad OTH exome AF: 0.0355

GnomAD4 exome AF: 0.0376 AC: 54669 AN: 1452376 Hom.: 5150 Cov.: 31 AF XY: 0.0360 AC XY: 26017 AN XY: 722048

Gnomad4 AFR exome AF: 0.512

Gnomad4 AMR exome AF: 0.0352

Gnomad4 ASJ exome AF: 0.0238

Gnomad4 EAS exome AF: 0.0354

Gnomad4 SAS exome AF: 0.0452

Gnomad4 FIN exome AF: 0.00503

Gnomad4 NFE exome AF: 0.0241

Gnomad4 OTH exome AF: 0.0534

GnomAD4 genome AF: 0.154 AC: 23404 AN: 152086 Hom.: 5081 Cov.: 32 AF XY: 0.148 AC XY: 11020 AN XY: 74342

Gnomad4 AFR AF: 0.485

Gnomad4 AMR AF: 0.0652

Gnomad4 ASJ AF: 0.0196

Gnomad4 EAS AF: 0.0414

Gnomad4 SAS AF: 0.0458

Gnomad4 FIN AF: 0.00245

Gnomad4 NFE AF: 0.0222

Gnomad4 OTH AF: 0.114

Alfa AF: 0.0708 Hom.: 1206

Bravo AF: 0.173

Asia WGS AF: 0.0640 AC: 225 AN: 3478

EpiCase AF: 0.0243

EpiControl AF: 0.0256

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

May 24, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:2

May 09, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Aug 23, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Leu784Leu in exon 20 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 48.80% (5077/10404) of African chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.br oadinstitute.org; dbSNP rs1126786). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	3.7
DANN	Benign	0.69
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs1126786; hg19: chr12-15776095; COSMIC: COSV55531114; COSMIC: COSV55531114;