rs17335738

Variant names:

• chr7-55019446-G-T
• rs17335738
• NM_005228.5:c.88+81G>T

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.88+81G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.147 in 918,674 control chromosomes in the GnomAD database, including 10,697 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1639 hom., cov: 33)
  • Exomes 𝑓: 0.15 (9058 hom.)
• Consequence: EGFR NM_005228.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.295
• Publications: 5 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=-0.56).
• BP6: Variant 7-55019446-G-T is Benign according to our data. Variant chr7-55019446-G-T is described in ClinVar as Benign. ClinVar VariationId is 1263180.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.185 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EGFR	NM_005228.5	c.88+81G>T		intron_variant	Intron 1 of 27	ENST00000275493.7	NP_005219.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EGFR	ENST00000275493.7	c.88+81G>T		intron_variant	Intron 1 of 27	1	NM_005228.5	ENSP00000275493.2

Frequencies

GnomAD3 genomes AF: 0.144 AC: 21778 AN: 150848 Hom.: 1635 Cov.: 33

Gnomad AFR AF: 0.156

Gnomad AMI AF: 0.0321

Gnomad AMR AF: 0.190

Gnomad ASJ AF: 0.101

Gnomad EAS AF: 0.00217

Gnomad SAS AF: 0.0491

Gnomad FIN AF: 0.176

Gnomad MID AF: 0.0757

Gnomad NFE AF: 0.144

Gnomad OTH AF: 0.119

GnomAD4 exome AF: 0.148 AC: 113646 AN: 767718 Hom.: 9058 AF XY: 0.149 AC XY: 55221 AN XY: 371462

African (AFR) AF: 0.172 AC: 2600 AN: 15106

American (AMR) AF: 0.245 AC: 1273 AN: 5188

Ashkenazi Jewish (ASJ) AF: 0.115 AC: 998 AN: 8712

East Asian (EAS) AF: 0.000817 AC: 12 AN: 14682

South Asian (SAS) AF: 0.0613 AC: 920 AN: 15000

European-Finnish (FIN) AF: 0.201 AC: 4230 AN: 21058

Middle Eastern (MID) AF: 0.0602 AC: 120 AN: 1992

European-Non Finnish (NFE) AF: 0.152 AC: 99466 AN: 656390

Other (OTH) AF: 0.136 AC: 4027 AN: 29590

GnomAD4 genome AF: 0.144 AC: 21813 AN: 150956 Hom.: 1639 Cov.: 33 AF XY: 0.146 AC XY: 10738 AN XY: 73756

African (AFR) AF: 0.156 AC: 6450 AN: 41298

American (AMR) AF: 0.191 AC: 2896 AN: 15188

Ashkenazi Jewish (ASJ) AF: 0.101 AC: 349 AN: 3460

East Asian (EAS) AF: 0.00218 AC: 11 AN: 5048

South Asian (SAS) AF: 0.0490 AC: 234 AN: 4776

European-Finnish (FIN) AF: 0.176 AC: 1811 AN: 10298

Middle Eastern (MID) AF: 0.0810 AC: 23 AN: 284

European-Non Finnish (NFE) AF: 0.144 AC: 9757 AN: 67608

Other (OTH) AF: 0.121 AC: 253 AN: 2092

Alfa AF: 0.142 Hom.: 182

Bravo AF: 0.146

Asia WGS AF: 0.0500 AC: 173 AN: 3448

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Feb 11, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	14
DANN	Benign	0.95
PhyloP100		-0.29
PromoterAI		-0.23	Neutral
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: rs17335738; hg19: chr7-55087139;