12-15621360-C-T

Position:

• chr12-15621360-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000281172.10(EPS8):​c.2426G>A​(p.Ser809Asn) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. S809S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: EPS8 ENST00000281172.10 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.28

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19319314).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EPS8	NM_004447.6	c.2426G>A	p.Ser809Asn	missense_variant	21/21	ENST00000281172.10	NP_004438.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EPS8	ENST00000281172.10	c.2426G>A	p.Ser809Asn	missense_variant	21/21	1	NM_004447.6	ENSP00000281172	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 27, 2023

The c.2426G>A (p.S809N) alteration is located in exon 21 (coding exon 20) of the EPS8 gene. This alteration results from a G to A substitution at nucleotide position 2426, causing the serine (S) at amino acid position 809 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T;T;T;T;.;T;T;T;T;.;T;T;.;.
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.88	.;.;.;.;D;.;.;.;.;D;.;D;.;D
M_CAP	Benign	0.0076	T
MetaRNN	Benign	0.19	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N;N;N;N;.;N;N;N;N;.;N;N;.;.
MutationTaster	Benign	0.98	D;D;D;D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-0.36	N;.;N;.;.;.;.;.;.;.;.;N;N;N
REVEL	Benign	0.068
Sift	Benign	0.036	D;.;D;.;.;.;.;.;.;.;.;D;D;D
Sift4G	Benign	0.30	T;.;T;.;.;.;.;.;.;.;.;T;T;T
Polyphen		0.65	P;P;P;P;.;P;P;P;P;.;P;P;.;.
Vest4		0.18
MutPred		0.092		Loss of phosphorylation at S809 (P = 0.0053);Loss of phosphorylation at S809 (P = 0.0053);Loss of phosphorylation at S809 (P = 0.0053);Loss of phosphorylation at S809 (P = 0.0053);.;Loss of phosphorylation at S809 (P = 0.0053);Loss of phosphorylation at S809 (P = 0.0053);Loss of phosphorylation at S809 (P = 0.0053);Loss of phosphorylation at S809 (P = 0.0053);.;Loss of phosphorylation at S809 (P = 0.0053);Loss of phosphorylation at S809 (P = 0.0053);.;.;
MVP		0.27
MPC		0.29
ClinPred		0.54	D
GERP RS		5.5
Varity_R		0.14
gMVP		0.20

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-15774294;