7-55019288-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_005228.5(EGFR):​c.11C>A​(p.Ser4Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000148 in 1,354,588 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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. S4C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000015 ( 0 hom. )

Consequence

EGFR
NM_005228.5 missense

Scores

2
2
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.142
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]

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ACMG classification

Classification made for transcript

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=0.27177566).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
EGFRNM_005228.5 linkuse as main transcriptc.11C>A p.Ser4Tyr missense_variant 1/28 ENST00000275493.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
EGFRENST00000275493.7 linkuse as main transcriptc.11C>A p.Ser4Tyr missense_variant 1/281 NM_005228.5 P1P00533-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.00000636
AC:
1
AN:
157216
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
88342
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000394
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000148
AC:
2
AN:
1354588
Hom.:
0
Cov.:
30
AF XY:
0.00
AC XY:
0
AN XY:
671606
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000281
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:
9.48e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

EGFR-related lung cancer Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpSep 13, 2022This sequence change replaces serine, which is neutral and polar, with tyrosine, which is neutral and polar, at codon 4 of the EGFR protein (p.Ser4Tyr). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with EGFR-related conditions. ClinVar contains an entry for this variant (Variation ID: 957645). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0". The tyrosine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.13
BayesDel_addAF
Benign
-0.10
T
BayesDel_noAF
Benign
-0.39
CADD
Benign
14
DANN
Uncertain
0.99
DEOGEN2
Benign
0.24
T;.;T;.;.;T
Eigen
Benign
-0.81
Eigen_PC
Benign
-0.88
FATHMM_MKL
Benign
0.029
N
LIST_S2
Benign
0.66
T;T;T;T;T;T
M_CAP
Pathogenic
0.98
D
MetaRNN
Benign
0.27
T;T;T;T;T;T
MetaSVM
Benign
-0.69
T
MutationAssessor
Benign
1.2
.;L;.;L;L;L
MutationTaster
Benign
1.0
N;N;N;N;N;N
PrimateAI
Pathogenic
0.83
D
PROVEAN
Benign
-0.28
N;N;.;N;N;N
REVEL
Benign
0.13
Sift
Uncertain
0.020
D;D;.;D;D;D
Sift4G
Benign
0.25
T;D;T;D;D;T
Polyphen
0.0
B;B;.;B;B;B
Vest4
0.15
MutPred
0.31
Loss of disorder (P = 0.001);Loss of disorder (P = 0.001);Loss of disorder (P = 0.001);Loss of disorder (P = 0.001);Loss of disorder (P = 0.001);Loss of disorder (P = 0.001);
MVP
0.76
MPC
1.6
ClinPred
0.056
T
GERP RS
-0.19
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.0
Varity_R
0.041
gMVP
0.53

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

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

Other links and lift over

dbSNP: rs771210838; hg19: chr7-55086981; API