7-55161509-C-T
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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
NM_005228.5 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.215
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 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 | 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 | c.1509C>T | p.Gly503= | synonymous_variant | 13/28 | 1 | NM_005228.5 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00839 AC: 1278AN: 152264Hom.: 12 Cov.: 34
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GnomAD3 exomes AF: 0.00758 AC: 1902AN: 250984Hom.: 12 AF XY: 0.00783 AC XY: 1063AN XY: 135674
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GnomAD4 exome AF: 0.0116 AC: 17009AN: 1461676Hom.: 102 Cov.: 31 AF XY: 0.0114 AC XY: 8300AN XY: 727170
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GnomAD4 genome AF: 0.00839 AC: 1278AN: 152382Hom.: 12 Cov.: 34 AF XY: 0.00805 AC XY: 600AN XY: 74512
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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
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at