chr7-55161509-C-T

Position:

chr7-55161509-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_005228.5(EGFR):c.1509C>T(p.Gly503=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0113 in 1,614,058 control chromosomes in the GnomAD database, including 114 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0084 ( 12 hom., cov: 34)

Exomes 𝑓: 0.012 ( 102 hom. )

Consequence

EGFR
NM_005228.5 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.215

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.73).

BP6

Variant 7-55161509-C-T is Benign according to our data. Variant chr7-55161509-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 695386.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-55161509-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.215 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00839 (1278/152382) while in subpopulation NFE AF= 0.0129 (879/68044). AF 95% confidence interval is 0.0122. There are 12 homozygotes in gnomad4. There are 600 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EGFR	NM_005228.5 linkuse as main transcript	c.1509C>T	p.Gly503=	synonymous_variant	13/28	ENST00000275493.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EGFR	ENST00000275493.7 linkuse as main transcript	c.1509C>T	p.Gly503=	synonymous_variant	13/28	1	NM_005228.5	P1	P00533-1

Frequencies

GnomAD3 genomes

AF:

0.00839

AC:

1278

AN:

152264

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00222

Gnomad AMI

AF:

0.0110

Gnomad AMR

AF:

0.00765

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.0136

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0129

Gnomad OTH

AF:

0.00956

GnomAD3 exomes

AF:

0.00758

AC:

1902

AN:

250984

Hom.:

AF XY:

0.00783

AC XY:

1063

AN XY:

135674

show subpopulations

Gnomad AFR exome

AF:

0.00135

Gnomad AMR exome

AF:

0.00460

Gnomad ASJ exome

AF:

0.00258

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00219

Gnomad FIN exome

AF:

0.0140

Gnomad NFE exome

AF:

0.0111

Gnomad OTH exome

AF:

0.0106

GnomAD4 exome

AF:

0.0116

AC:

17009

AN:

1461676

Hom.:

102

Cov.:

AF XY:

0.0114

AC XY:

8300

AN XY:

727170

show subpopulations

Gnomad4 AFR exome

AF:

0.00140

Gnomad4 AMR exome

AF:

0.00476

Gnomad4 ASJ exome

AF:

0.00214

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00195

Gnomad4 FIN exome

AF:

0.0141

Gnomad4 NFE exome

AF:

0.0136

Gnomad4 OTH exome

AF:

0.0103

GnomAD4 genome

AF:

0.00839

AC:

1278

AN:

152382

Hom.:

Cov.:

AF XY:

0.00805

AC XY:

600

AN XY:

74512

show subpopulations

Gnomad4 AFR

AF:

0.00221

Gnomad4 AMR

AF:

0.00764

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00145

Gnomad4 FIN

AF:

0.0136

Gnomad4 NFE

AF:

0.0129

Gnomad4 OTH

AF:

0.00946

Alfa

AF:

0.0101

Hom.:

Bravo

AF:

0.00749

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.00998

EpiControl

AF:

0.0108

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 15, 2020	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2024	EGFR: BP4, BP7, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 16, 2023	- -

not specified

Benign:2

Benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The EGFR p.Gly503Gly variant was identified in the literature in a Korean cohort of 27 lung cancer cases (frequency: 0.41) and 27 controls (frequency: 0.41) (Choi_2007_PMID:12956637). The variant was also identified in a case report of an individual with suspected plasma cell neoplasm (Peterson_2019_PMID:31320253). The variant was identified in dbSNP (ID: rs17336800), ClinVar (classified as benign by Invitae) and LOVD 3.0, but was not identified in Cosmic. The variant was identified in control databases in 2092 of 267912 chromosomes (14 homozygous) at a frequency of 0.007809 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (Finnish) in 348 of 24930 chromosomes (freq: 0.01396), European (non-Finnish) in 1370 of 117988 chromosomes (freq: 0.01161), Other in 75 of 6696 chromosomes (freq: 0.0112), Latino in 163 of 35096 chromosomes (freq: 0.004644), Ashkenazi Jewish in 24 of 9852 chromosomes (freq: 0.002436), South Asian in 67 of 30502 chromosomes (freq: 0.002197) and African in 45 of 23606 chromosomes (freq: 0.001906), but was not observed in the East Asian population. The p.Gly503Gly variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. However, three of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing and the creation of a new 5' splice site. However, this has not been confirmed by RNA analysis and is not predictive enough to assume pathogenicity. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 26, 2021	- -

EGFR-related lung cancer

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.73

CADD

Benign

2.6

DANN

Benign

0.44

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.11

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over