12-15623283-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004447.6(EPS8):c.2230G>A(p.Val744Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00253 in 1,569,038 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V744A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0024 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0025 (6 hom.)
• Consequence: EPS8 NM_004447.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.84

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 (MetaRNN=0.008447826).
• BP6: Variant 12-15623283-C-T is Benign according to our data. Variant chr12-15623283-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 506478.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00238 (349/146848) while in subpopulation NFE AF= 0.00372 (251/67502). AF 95% confidence interval is 0.00334. There are 0 homozygotes in gnomad4. There are 161 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPS8	NM_004447.6	c.2230G>A	p.Val744Ile	missense_variant	20/21	ENST00000281172.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPS8	ENST00000281172.10	c.2230G>A	p.Val744Ile	missense_variant	20/21	1	NM_004447.6	P1

Frequencies

GnomAD3 genomes AF: 0.00238 AC: 349 AN: 146746 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000687

Gnomad AMI AF: 0.00442

Gnomad AMR AF: 0.00313

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000611

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00372

Gnomad OTH AF: 0.00392

GnomAD3 exomes AF: 0.00205 AC: 438 AN: 213728 Hom.: 3 AF XY: 0.00200 AC XY: 233 AN XY: 116478

Gnomad AFR exome AF: 0.000342

Gnomad AMR exome AF: 0.00230

Gnomad ASJ exome AF: 0.00248

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00104

Gnomad NFE exome AF: 0.00307

Gnomad OTH exome AF: 0.00429

GnomAD4 exome AF: 0.00254 AC: 3615 AN: 1422190 Hom.: 6 Cov.: 30 AF XY: 0.00252 AC XY: 1780 AN XY: 707702

Gnomad4 AFR exome AF: 0.000454

Gnomad4 AMR exome AF: 0.00247

Gnomad4 ASJ exome AF: 0.00258

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000125

Gnomad4 FIN exome AF: 0.00116

Gnomad4 NFE exome AF: 0.00294

Gnomad4 OTH exome AF: 0.00285

GnomAD4 genome AF: 0.00238 AC: 349 AN: 146848 Hom.: 0 Cov.: 32 AF XY: 0.00225 AC XY: 161 AN XY: 71598

Gnomad4 AFR AF: 0.000685

Gnomad4 AMR AF: 0.00313

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000611

Gnomad4 NFE AF: 0.00372

Gnomad4 OTH AF: 0.00388

Alfa AF: 0.00305 Hom.: 3

Bravo AF: 0.00233

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00234 AC: 9

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00326 AC: 28

ExAC AF: 0.00185 AC: 224

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 25, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 19, 2024	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 07, 2018

p.Val744Ile in exon 20 of EPS8: This variant is classified as likely benign beca use it has been identified in 0.3% (355/114830) of European chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs7 7967764). In addition, computational prediction tools and conservation analyses do not suggest a high likelihood of impact to the protein. ACMG/AMP Criteria ap plied: BS1, BP4. -

EPS8-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 19, 2022

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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.40
Cadd	Benign	20
Dann	Uncertain	1.0
DEOGEN2	Benign	0.25	T;T;T;T;.;T;T;T;T;.;T;T;.;.
Eigen	Benign	0.097
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.92	D
MetaRNN	Benign	0.0084	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L;L;L;L;.;L;L;L;L;.;L;L;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-0.56	N;.;N;.;.;.;.;.;.;.;.;N;N;N
REVEL	Benign	0.13
Sift	Benign	0.047	D;.;D;.;.;.;.;.;.;.;.;D;D;D
Sift4G	Benign	0.15	T;.;T;.;.;.;.;.;.;.;.;T;D;D
Polyphen		0.16	B;B;B;B;.;B;B;B;B;.;B;B;.;.
Vest4		0.18
MVP		0.30
MPC		0.29
ClinPred		0.015	T
GERP RS		5.7
Varity_R		0.097
gMVP		0.38

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: rs77967764; hg19: chr12-15776217; COSMIC: COSV99843248;