rs121913420

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP5

The NM_005228.5(EGFR):​c.2200G>A​(p.Glu734Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,594 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (no stars).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

EGFR
NM_005228.5 missense

Scores

4
11
4

Clinical Significance

Likely pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 9.89
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM1
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 11 uncertain in NM_005228.5
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 7-55174737-G-A is Pathogenic according to our data. Variant chr7-55174737-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 376077.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
EGFRNM_005228.5 linkuse as main transcriptc.2200G>A p.Glu734Lys missense_variant 19/28 ENST00000275493.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
EGFRENST00000275493.7 linkuse as main transcriptc.2200G>A p.Glu734Lys missense_variant 19/281 NM_005228.5 P1P00533-1
EGFRENST00000455089.5 linkuse as main transcriptc.2065G>A p.Glu689Lys missense_variant 18/261
EGFRENST00000450046.2 linkuse as main transcriptc.2041G>A p.Glu681Lys missense_variant 19/284
EGFRENST00000700145.1 linkuse as main transcriptc.550G>A p.Glu184Lys missense_variant 6/9

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461594
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
727110
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Non-small cell lung carcinoma Pathogenic:1
Likely pathogenic, no assertion criteria providedliterature onlyDatabase of Curated Mutations (DoCM)Jul 14, 2015- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.83
BayesDel_addAF
Pathogenic
0.21
D
BayesDel_noAF
Uncertain
0.060
CADD
Pathogenic
34
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.68
D;D;D
Eigen
Uncertain
0.52
Eigen_PC
Uncertain
0.63
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Uncertain
0.97
D;D;D
M_CAP
Benign
0.085
D
MetaRNN
Uncertain
0.74
D;D;D
MetaSVM
Benign
-0.42
T
MutationAssessor
Benign
0.97
.;.;L
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Pathogenic
0.84
D
PROVEAN
Uncertain
-3.3
D;.;D
REVEL
Uncertain
0.52
Sift
Uncertain
0.0020
D;.;D
Sift4G
Uncertain
0.052
T;T;T
Polyphen
0.69
P;.;D
Vest4
0.74
MutPred
0.52
.;.;Gain of methylation at E734 (P = 0.0067);
MVP
0.87
MPC
1.5
ClinPred
0.99
D
GERP RS
5.6
Varity_R
0.92
gMVP
0.68

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.070
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs121913420; hg19: chr7-55242430; COSMIC: COSV51798694; COSMIC: COSV51798694; API