rs121913431

Positions:

• chr7-55181438-G-A
• chr7-55181438-G-C
• chr7-55181438-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP3_Moderate PP5

The ENST00000275493.7(EGFR):​c.2429G>A​(p.Gly810Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G810S) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 34)
• Consequence: EGFR ENST00000275493.7 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.96

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]

EGFR-AS1 (HGNC:40207): (EGFR antisense RNA 1)

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a domain Protein kinase (size 267) in uniprot entity EGFR_HUMAN there are 56 pathogenic changes around while only 8 benign (88%) in ENST00000275493.7
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr7-55181437-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 376278.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.842
• PP5: Variant 7-55181438-G-A is Pathogenic according to our data. Variant chr7-55181438-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 376279.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EGFR	NM_005228.5	c.2429G>A	p.Gly810Asp	missense_variant	20/28	ENST00000275493.7	NP_005219.2
EGFR-AS1	NR_047551.1	n.1133C>T		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EGFR	ENST00000275493.7	c.2429G>A	p.Gly810Asp	missense_variant	20/28	1	NM_005228.5	ENSP00000275493	P1
EGFR-AS1	ENST00000442411.2	n.1161C>T		non_coding_transcript_exon_variant	2/2	2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 34

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Squamous cell carcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

Jul 14, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.69	D;D;D
Eigen	Uncertain	0.58
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.95	D;D;D
M_CAP	Benign	0.034	D
MetaRNN	Pathogenic	0.84	D;D;D
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	0.67	.;.;N
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-5.8	D;.;D
REVEL	Uncertain	0.49
Sift	Benign	0.066	T;.;T
Sift4G	Benign	0.079	T;T;T
Polyphen		0.62	P;.;D
Vest4		0.92
MutPred		0.42		.;.;Loss of ubiquitination at K806 (P = 0.0863);
MVP		0.88
MPC		1.7
ClinPred		0.99	D
GERP RS		5.9
Varity_R		0.96
gMVP		0.85

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: rs121913431; hg19: chr7-55249131; COSMIC: COSV51789261;