12-15623261-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004447.6(EPS8):c.2252A>G(p.Asn751Ser) 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 (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: EPS8 NM_004447.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.41

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29217064).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EPS8	NM_004447.6	c.2252A>G	p.Asn751Ser	missense_variant	20/21	ENST00000281172.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EPS8	ENST00000281172.10	c.2252A>G	p.Asn751Ser	missense_variant	20/21	1	NM_004447.6	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 07, 2022

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.65
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.22	T;T;T;T;.;T;T;T;T;.;T;T;.;.
Eigen	Benign	-0.17
Eigen_PC	Benign	0.043
FATHMM_MKL	Uncertain	0.92	D
M_CAP	Benign	0.0076	T
MetaRNN	Benign	0.29	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.28	N;N;N;N;.;N;N;N;N;.;N;N;.;.
MutationTaster	Benign	0.84	D;D;D;D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.63	N;.;N;.;.;.;.;.;.;.;.;N;N;N
REVEL	Benign	0.11
Sift	Benign	0.054	T;.;T;.;.;.;.;.;.;.;.;T;D;D
Sift4G	Benign	0.10	T;.;T;.;.;.;.;.;.;.;.;T;T;T
Polyphen		0.0050	B;B;B;B;.;B;B;B;B;.;B;B;.;.
Vest4		0.10
MutPred		0.77		Gain of catalytic residue at L747 (P = 0.1774);Gain of catalytic residue at L747 (P = 0.1774);Gain of catalytic residue at L747 (P = 0.1774);Gain of catalytic residue at L747 (P = 0.1774);.;Gain of catalytic residue at L747 (P = 0.1774);Gain of catalytic residue at L747 (P = 0.1774);Gain of catalytic residue at L747 (P = 0.1774);Gain of catalytic residue at L747 (P = 0.1774);.;Gain of catalytic residue at L747 (P = 0.1774);Gain of catalytic residue at L747 (P = 0.1774);.;.;
MVP		0.44
MPC		0.094
ClinPred		0.53	D
GERP RS		2.6
Varity_R		0.050
gMVP		0.31

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: chr12-15776195;