dbSNP rs749433287: EGFR:p.Pro3His (chr7-55019285-C-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_005228.5(EGFR):c.8C>A(p.Pro3His) 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. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P3S) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

EGFR
NM_005228.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0290

Publications

0 publications found

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]

EGFR Gene-Disease associations (from GenCC):

lung cancer
Inheritance: AD Classification: DEFINITIVE Submitted by: G2P, Ambry Genetics
non-small cell lung carcinoma
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
inflammatory skin and bowel disease, neonatal, 2
Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: G2P, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
neonatal inflammatory skin and bowel disease
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

EGFR links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.34108472).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005228.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EGFR	NM_005228.5	MANE Select	c.8C>A	p.Pro3His	missense	Exon 1 of 28	NP_005219.2
EGFR	NM_001346899.2		c.8C>A	p.Pro3His	missense	Exon 1 of 27	NP_001333828.1
EGFR	NM_001346898.2		c.8C>A	p.Pro3His	missense	Exon 1 of 27	NP_001333827.1	E7BSV0

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EGFR	ENST00000275493.7	TSL:1 MANE Select	c.8C>A	p.Pro3His	missense	Exon 1 of 28	ENSP00000275493.2	P00533-1
EGFR	ENST00000455089.5	TSL:1	c.8C>A	p.Pro3His	missense	Exon 1 of 26	ENSP00000415559.1	Q504U8
EGFR	ENST00000344576.7	TSL:1	c.8C>A	p.Pro3His	missense	Exon 1 of 16	ENSP00000345973.2	P00533-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1353762

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

671188

African (AFR)

AF:

0.00

AC:

AN:

27834

American (AMR)

AF:

0.00

AC:

AN:

35524

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22852

East Asian (EAS)

AF:

0.00

AC:

AN:

30218

South Asian (SAS)

AF:

0.00

AC:

AN:

77484

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46252

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5008

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1054098

Other (OTH)

AF:

0.00

AC:

AN:

54492

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.060

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.27

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.43

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.68

M_CAP

Pathogenic

0.98

MetaRNN

Benign

0.34

MetaSVM

Benign

-0.63

MutationAssessor

Benign

0.69

PhyloP100

0.029

PrimateAI

Pathogenic

0.79

PROVEAN

Benign

-0.83

REVEL

Benign

0.26

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.043

Polyphen

0.85

Vest4

0.29

MutPred

0.22

Loss of catalytic residue at P3 (P = 0.0655)

MVP

0.77

MPC

0.81

ClinPred

0.30

GERP RS

1.4

PromoterAI

0.0099

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.090

gMVP

0.44

Mutation Taster

=60/40

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over