rs2075109

Variant names:

• chr7-55151210-T-C
• rs2075109
• NM_005228.5:c.560-84T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005228.5(EGFR):​c.560-84T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.527 in 1,315,558 control chromosomes in the GnomAD database, including 184,090 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.52 (20952 hom., cov: 33)
  • Exomes 𝑓: 0.53 (163138 hom.)
• Consequence: EGFR NM_005228.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.08
• Publications: 24 publications found

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 7-55151210-T-C is Benign according to our data. Variant chr7-55151210-T-C is described in ClinVar as Benign. ClinVar VariationId is 1265640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.548 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EGFR	NM_005228.5	c.560-84T>C		intron_variant	Intron 4 of 27	ENST00000275493.7	NP_005219.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EGFR	ENST00000275493.7	c.560-84T>C		intron_variant	Intron 4 of 27	1	NM_005228.5	ENSP00000275493.2

Frequencies

GnomAD3 genomes AF: 0.523 AC: 79418 AN: 151996 Hom.: 20916 Cov.: 33

Gnomad AFR AF: 0.554

Gnomad AMI AF: 0.522

Gnomad AMR AF: 0.501

Gnomad ASJ AF: 0.553

Gnomad EAS AF: 0.352

Gnomad SAS AF: 0.555

Gnomad FIN AF: 0.481

Gnomad MID AF: 0.456

Gnomad NFE AF: 0.524

Gnomad OTH AF: 0.514

GnomAD4 exome AF: 0.527 AC: 613507 AN: 1163444 Hom.: 163138 AF XY: 0.528 AC XY: 313572 AN XY: 593832

African (AFR) AF: 0.556 AC: 15297 AN: 27506

American (AMR) AF: 0.529 AC: 23358 AN: 44168

Ashkenazi Jewish (ASJ) AF: 0.566 AC: 13699 AN: 24198

East Asian (EAS) AF: 0.334 AC: 12723 AN: 38148

South Asian (SAS) AF: 0.565 AC: 45212 AN: 79986

European-Finnish (FIN) AF: 0.494 AC: 25666 AN: 52000

Middle Eastern (MID) AF: 0.535 AC: 2780 AN: 5192

European-Non Finnish (NFE) AF: 0.532 AC: 448232 AN: 841760

Other (OTH) AF: 0.526 AC: 26540 AN: 50486

GnomAD4 genome AF: 0.523 AC: 79520 AN: 152114 Hom.: 20952 Cov.: 33 AF XY: 0.517 AC XY: 38454 AN XY: 74350

African (AFR) AF: 0.554 AC: 22987 AN: 41482

American (AMR) AF: 0.502 AC: 7684 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.553 AC: 1920 AN: 3470

East Asian (EAS) AF: 0.352 AC: 1821 AN: 5172

South Asian (SAS) AF: 0.554 AC: 2661 AN: 4806

European-Finnish (FIN) AF: 0.481 AC: 5082 AN: 10562

Middle Eastern (MID) AF: 0.469 AC: 138 AN: 294

European-Non Finnish (NFE) AF: 0.524 AC: 35656 AN: 68000

Other (OTH) AF: 0.518 AC: 1096 AN: 2116

Alfa AF: 0.525 Hom.: 9056

Bravo AF: 0.524

Asia WGS AF: 0.475 AC: 1655 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jan 10, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.080
DANN	Benign	0.29
PhyloP100		-2.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2075109; hg19: chr7-55218903; COSMIC: COSV51801153; COSMIC: COSV51801153;