Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_005228.5(EGFR):c.1839C>T(p.Ala613Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0547 in 1,614,052 control chromosomes in the GnomAD database, including 2,548 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A613A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.054 ( 240 hom., cov: 33)

Exomes 𝑓: 0.055 ( 2308 hom. )

Consequence

EGFR
NM_005228.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.0530

Publications

26 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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
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: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.61).

BP6

Variant 7-55165396-C-T is Benign according to our data. Variant chr7-55165396-C-T is described in ClinVar as Benign. ClinVar VariationId is 360461.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.053 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0579 is higher than 0.05.

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
EGFR	NM_005228.5	MANE Select	c.1839C>T	p.Ala613Ala	synonymous	Exon 15 of 28	NP_005219.2
EGFR	NM_001346899.2		c.1704C>T	p.Ala568Ala	synonymous	Exon 14 of 27	NP_001333828.1
EGFR	NM_001346900.2		c.1680C>T	p.Ala560Ala	synonymous	Exon 15 of 28	NP_001333829.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
EGFR	ENST00000275493.7	TSL:1 MANE Select	c.1839C>T	p.Ala613Ala	synonymous	Exon 15 of 28	ENSP00000275493.2
EGFR	ENST00000455089.5	TSL:1	c.1704C>T	p.Ala568Ala	synonymous	Exon 14 of 26	ENSP00000415559.1
EGFR	ENST00000344576.7	TSL:1	c.1839C>T	p.Ala613Ala	synonymous	Exon 15 of 16	ENSP00000345973.2

Frequencies

GnomAD3 genomes

AF:

0.0545

AC:

8286

AN:

152156

Hom.:

240

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0537

Gnomad AMI

AF:

0.00548

Gnomad AMR

AF:

0.0481

Gnomad ASJ

AF:

0.0855

Gnomad EAS

AF:

0.00173

Gnomad SAS

AF:

0.0393

Gnomad FIN

AF:

0.0571

Gnomad MID

AF:

0.127

Gnomad NFE

AF:

0.0595

Gnomad OTH

AF:

0.0632

GnomAD2 exomes

AF:

0.0516

AC:

12966

AN:

251362

AF XY:

0.0515

show subpopulations

Gnomad AFR exome

AF:

0.0570

Gnomad AMR exome

AF:

0.0449

Gnomad ASJ exome

AF:

0.0713

Gnomad EAS exome

AF:

0.000435

Gnomad FIN exome

AF:

0.0568

Gnomad NFE exome

AF:

0.0618

Gnomad OTH exome

AF:

0.0593

GnomAD4 exome

AF:

0.0548

AC:

80053

AN:

1461778

Hom.:

2308

Cov.:

AF XY:

0.0547

AC XY:

39770

AN XY:

727190

show subpopulations

African (AFR)

AF:

0.0582

AC:

1948

AN:

33472

American (AMR)

AF:

0.0444

AC:

1984

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.0721

AC:

1883

AN:

26134

East Asian (EAS)

AF:

0.000705

AC:

AN:

39700

South Asian (SAS)

AF:

0.0391

AC:

3376

AN:

86256

European-Finnish (FIN)

AF:

0.0564

AC:

3010

AN:

53406

Middle Eastern (MID)

AF:

0.0887

AC:

511

AN:

5764

European-Non Finnish (NFE)

AF:

0.0574

AC:

63849

AN:

1111954

Other (OTH)

AF:

0.0574

AC:

3464

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

4309

8618

12928

17237

21546

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2314

4628

6942

9256

11570

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0544

AC:

8280

AN:

152274

Hom.:

240

Cov.:

AF XY:

0.0537

AC XY:

4000

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.0535

AC:

2224

AN:

41544

American (AMR)

AF:

0.0480

AC:

735

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0855

AC:

297

AN:

3472

East Asian (EAS)

AF:

0.00174

AC:

AN:

5178

South Asian (SAS)

AF:

0.0394

AC:

190

AN:

4826

European-Finnish (FIN)

AF:

0.0571

AC:

606

AN:

10610

Middle Eastern (MID)

AF:

0.122

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0595

AC:

4045

AN:

68024

Other (OTH)

AF:

0.0630

AC:

133

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

409

818

1227

1636

2045

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

184

276

368

460

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0613

Hom.:

126

Bravo

AF:

0.0538

Asia WGS

AF:

0.0250

AC:

AN:

3478

EpiCase

AF:

0.0640

EpiControl

AF:

0.0699

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

EGFR-related lung cancer (1)

Hereditary cancer-predisposing syndrome (1)

Lung cancer (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.61

CADD

Benign

8.5

(source)

DANN

Benign

0.45

PhyloP100

0.053

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over