7-55146674-C-G

Position:

• chr7-55146674-C-G

Variant summary

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

The NM_005228.5(EGFR):​c.493C>G​(p.Arg165Gly) 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. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R165W) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: EGFR NM_005228.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.192

Genes affected

EGFR (HGNC:3236): (epidermal growth factor receptor) The protein encoded by this gene is a transmembrane glycoprotein that is a member of the protein kinase superfamily. This protein is a receptor for members of the epidermal growth factor family. EGFR is a cell surface protein that binds to epidermal growth factor, thus inducing receptor dimerization and tyrosine autophosphorylation leading to cell proliferation. Mutations in this gene are associated with lung cancer. EGFR is a component of the cytokine storm which contributes to a severe form of Coronavirus Disease 2019 (COVID-19) resulting from infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). [provided by RefSeq, Jul 2020]

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=0.26892465).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EGFR	NM_005228.5	c.493C>G	p.Arg165Gly	missense_variant	4/28	ENST00000275493.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EGFR	ENST00000275493.7	c.493C>G	p.Arg165Gly	missense_variant	4/28	1	NM_005228.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

EGFR-related lung cancer Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 01, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with EGFR-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 165 of the EGFR protein (p.Arg165Gly). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.012	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.73	.;.;.;D;D
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.16	N
LIST_S2	Uncertain	0.90	D;D;D;T;D
M_CAP	Uncertain	0.094	D
MetaRNN	Benign	0.27	T;T;T;T;T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	0.83	L;L;L;L;.
MutationTaster	Benign	1.0	D;N;N;N;N;N;N
PrimateAI	Benign	0.21	T
PROVEAN	Uncertain	-2.9	D;D;D;N;N
REVEL	Uncertain	0.33
Sift	Benign	0.040	D;D;D;T;T
Sift4G	Benign	0.34	T;T;T;T;T
Polyphen		0.0010	B;B;B;B;.
Vest4		0.23
MutPred		0.66		Loss of stability (P = 0.059);Loss of stability (P = 0.059);Loss of stability (P = 0.059);Loss of stability (P = 0.059);.;
MVP		0.76
MPC		0.76
ClinPred		0.30	T
GERP RS		2.4
Varity_R		0.35
gMVP		0.58

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: rs587778252; hg19: chr7-55214367;