12-15623230-A-C

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.2283T>G(p.Asp761Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00794 in 1,613,380 control chromosomes in the GnomAD database, including 82 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 Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0075 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0080 (77 hom.)
• Consequence: EPS8 NM_004447.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.221

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=0.0072618723).
• BP6: Variant 12-15623230-A-C is Benign according to our data. Variant chr12-15623230-A-C is described in ClinVar as [Benign]. Clinvar id is 499499.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-15623230-A-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00746 (1136/152184) while in subpopulation AMR AF= 0.0143 (219/15286). AF 95% confidence interval is 0.0128. There are 5 homozygotes in gnomad4. There are 545 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPS8	NM_004447.6	c.2283T>G	p.Asp761Glu	missense_variant	20/21	ENST00000281172.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPS8	ENST00000281172.10	c.2283T>G	p.Asp761Glu	missense_variant	20/21	1	NM_004447.6	P1

Frequencies

GnomAD3 genomes AF: 0.00746 AC: 1134 AN: 152070 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.00121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0143

Gnomad ASJ AF: 0.0297

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00561

Gnomad FIN AF: 0.00217

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0101

Gnomad OTH AF: 0.0110

GnomAD3 exomes AF: 0.00721 AC: 1809 AN: 251016 Hom.: 17 AF XY: 0.00748 AC XY: 1015 AN XY: 135680

Gnomad AFR exome AF: 0.00135

Gnomad AMR exome AF: 0.00530

Gnomad ASJ exome AF: 0.0250

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00772

Gnomad FIN exome AF: 0.00263

Gnomad NFE exome AF: 0.00880

Gnomad OTH exome AF: 0.00997

GnomAD4 exome AF: 0.00799 AC: 11678 AN: 1461196 Hom.: 77 Cov.: 30 AF XY: 0.00805 AC XY: 5853 AN XY: 726920

Gnomad4 AFR exome AF: 0.00102

Gnomad4 AMR exome AF: 0.00604

Gnomad4 ASJ exome AF: 0.0260

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00769

Gnomad4 FIN exome AF: 0.00219

Gnomad4 NFE exome AF: 0.00838

Gnomad4 OTH exome AF: 0.00863

GnomAD4 genome AF: 0.00746 AC: 1136 AN: 152184 Hom.: 5 Cov.: 32 AF XY: 0.00732 AC XY: 545 AN XY: 74424

Gnomad4 AFR AF: 0.00120

Gnomad4 AMR AF: 0.0143

Gnomad4 ASJ AF: 0.0297

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00561

Gnomad4 FIN AF: 0.00217

Gnomad4 NFE AF: 0.0101

Gnomad4 OTH AF: 0.0113

Alfa AF: 0.0101 Hom.: 33

Bravo AF: 0.00793

TwinsUK AF: 0.0111 AC: 41

ALSPAC AF: 0.0122 AC: 47

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.0117 AC: 101

ExAC AF: 0.00736 AC: 893

Asia WGS AF: 0.00260 AC: 11 AN: 3478

EpiCase AF: 0.00993

EpiControl AF: 0.00914

ClinVar

Significance: 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	Dec 15, 2023	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	EPS8: BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 04, 2018	This variant is associated with the following publications: (PMID: 26721930) -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 23, 2017	p.Asp761Glu in exon 20 of EPS8: This variant is not expected to have clinical si gnificance because it has been identified in 0.98% (652/66712) of European chrom osomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ; dbSNP rs7137185). -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 26, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.61
Cadd	Benign	4.9
Dann	Benign	0.85
DEOGEN2	Benign	0.11	T;T;T;T;.;T;T;T;T;.;T;T;.;.
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.69	D
MetaRNN	Benign	0.0073	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.33	N;N;N;N;.;N;N;N;N;.;N;N;.;.
MutationTaster	Benign	0.98	D;D;D;D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	0.15	N;.;N;.;.;.;.;.;.;.;.;N;N;N
REVEL	Benign	0.15
Sift	Benign	0.99	T;.;T;.;.;.;.;.;.;.;.;T;T;T
Sift4G	Benign	0.52	T;.;T;.;.;.;.;.;.;.;.;T;T;T
Polyphen		0.0	B;B;B;B;.;B;B;B;B;.;B;B;.;.
Vest4		0.22
MutPred		0.18		Gain of ubiquitination at K760 (P = 0.0945);Gain of ubiquitination at K760 (P = 0.0945);Gain of ubiquitination at K760 (P = 0.0945);Gain of ubiquitination at K760 (P = 0.0945);.;Gain of ubiquitination at K760 (P = 0.0945);Gain of ubiquitination at K760 (P = 0.0945);Gain of ubiquitination at K760 (P = 0.0945);Gain of ubiquitination at K760 (P = 0.0945);.;Gain of ubiquitination at K760 (P = 0.0945);Gain of ubiquitination at K760 (P = 0.0945);.;.;
MVP		0.31
MPC		0.11
ClinPred		0.0059	T
GERP RS		1.9
Varity_R		0.042
gMVP		0.24

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs7137185; hg19: chr12-15776164;