NM_005228.5:c.2283+69G>A

Variant names:

• chr7-55174889-G-A
• rs17337135
• NM_005228.5:c.2283+69G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005228.5(EGFR):​c.2283+69G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0222 in 1,243,416 control chromosomes in the GnomAD database, including 389 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (33 hom., cov: 33)
  • Exomes 𝑓: 0.023 (356 hom.)
• Consequence: EGFR NM_005228.5 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.724
• Publications: 6 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=-0.79).
• BP6: Variant 7-55174889-G-A is Benign according to our data. Variant chr7-55174889-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 1191430.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0192 (2931/152286) while in subpopulation NFE AF = 0.0276 (1880/68030). AF 95% confidence interval is 0.0266. There are 33 homozygotes in GnomAd4. There are 1311 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 33 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EGFR	NM_005228.5	c.2283+69G>A		intron_variant	Intron 19 of 27	ENST00000275493.7	NP_005219.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EGFR	ENST00000275493.7	c.2283+69G>A		intron_variant	Intron 19 of 27	1	NM_005228.5	ENSP00000275493.2
EGFR	ENST00000455089.5	c.2148+69G>A		intron_variant	Intron 18 of 25	1		ENSP00000415559.1
EGFR	ENST00000450046.2	c.2124+69G>A		intron_variant	Intron 19 of 27	4		ENSP00000413354.2
EGFR	ENST00000700145.1	c.630+69G>A		intron_variant	Intron 6 of 8			ENSP00000514824.1

Frequencies

GnomAD3 genomes AF: 0.0193 AC: 2935 AN: 152168 Hom.: 33 Cov.: 33

Gnomad AFR AF: 0.00990

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.0182

Gnomad ASJ AF: 0.0383

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0149

Gnomad FIN AF: 0.00697

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0277

Gnomad OTH AF: 0.0254

GnomAD4 exome AF: 0.0227 AC: 24725 AN: 1091130 Hom.: 356 AF XY: 0.0227 AC XY: 12685 AN XY: 559150

African (AFR) AF: 0.00934 AC: 243 AN: 26016

American (AMR) AF: 0.0157 AC: 681 AN: 43402

Ashkenazi Jewish (ASJ) AF: 0.0334 AC: 790 AN: 23660

East Asian (EAS) AF: 0.0000264 AC: 1 AN: 37834

South Asian (SAS) AF: 0.0156 AC: 1219 AN: 78330

European-Finnish (FIN) AF: 0.00885 AC: 463 AN: 52292

Middle Eastern (MID) AF: 0.0455 AC: 230 AN: 5054

European-Non Finnish (NFE) AF: 0.0257 AC: 19912 AN: 776182

Other (OTH) AF: 0.0245 AC: 1186 AN: 48360

GnomAD4 genome AF: 0.0192 AC: 2931 AN: 152286 Hom.: 33 Cov.: 33 AF XY: 0.0176 AC XY: 1311 AN XY: 74450

African (AFR) AF: 0.00984 AC: 409 AN: 41552

American (AMR) AF: 0.0182 AC: 278 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0383 AC: 133 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5188

South Asian (SAS) AF: 0.0149 AC: 72 AN: 4818

European-Finnish (FIN) AF: 0.00697 AC: 74 AN: 10612

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.0276 AC: 1880 AN: 68030

Other (OTH) AF: 0.0256 AC: 54 AN: 2112

Alfa AF: 0.0279 Hom.: 12

Bravo AF: 0.0202

Asia WGS AF: 0.00925 AC: 32 AN: 3474

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 16, 2019

GeneDx

Significance: Likely 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	-0.79
CADD	Benign	3.9
DANN	Benign	0.63
PhyloP100		0.72
Mutation Taster		=100/0	polymorphism

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: rs17337135; hg19: chr7-55242582; COSMIC: COSV51791282;