NM_004447.6:c.2292G>T

Variant names:

• chr12-15623221-C-A
• NM_004447.6:c.2292G>T

Variant summary

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

The NM_004447.6(EPS8):​c.2292G>T​(p.Arg764Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts 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: 0.783

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=0.32442802).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EPS8	NM_004447.6	c.2292G>T	p.Arg764Ser	missense_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.2292G>T	p.Arg764Ser	missense_variant	Exon 20 of 21	1	NM_004447.6	ENSP00000281172.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Jun 16, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2292G>T (p.R764S) alteration is located in exon 20 (coding exon 19) of the EPS8 gene. This alteration results from a G to T substitution at nucleotide position 2292, causing the arginine (R) at amino acid position 764 to be replaced by a serine (S). 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	Pathogenic	0.84
BayesDel_addAF	Benign	-0.050	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.76	D;D;D;D;.;D;D;D;D;.;D;D;.;.
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.16
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.89	.;.;.;.;D;.;.;.;.;D;.;D;.;D
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.32	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.4	M;M;M;M;.;M;M;M;M;.;M;M;.;.
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-3.1	D;.;D;.;.;.;.;.;.;.;.;D;D;D
REVEL	Benign	0.16
Sift	Uncertain	0.0030	D;.;D;.;.;.;.;.;.;.;.;D;D;D
Sift4G	Uncertain	0.0070	D;.;D;.;.;.;.;.;.;.;.;D;D;D
Polyphen		0.12	B;B;B;B;.;B;B;B;B;.;B;B;.;.
Vest4		0.51
MutPred		0.43		Gain of ubiquitination at K760 (P = 0.0766);Gain of ubiquitination at K760 (P = 0.0766);Gain of ubiquitination at K760 (P = 0.0766);Gain of ubiquitination at K760 (P = 0.0766);.;Gain of ubiquitination at K760 (P = 0.0766);Gain of ubiquitination at K760 (P = 0.0766);Gain of ubiquitination at K760 (P = 0.0766);Gain of ubiquitination at K760 (P = 0.0766);.;Gain of ubiquitination at K760 (P = 0.0766);Gain of ubiquitination at K760 (P = 0.0766);.;.;
MVP		0.54
MPC		0.14
ClinPred		0.94	D
GERP RS		2.8
Varity_R		0.35
gMVP		0.56

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: chr12-15776155;