rs4947986

Positions:

• chr7-55153962-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000275493.7(EGFR):​c.748-49G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.283 in 1,613,446 control chromosomes in the GnomAD database, including 70,446 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (5602 hom., cov: 32)
  • Exomes 𝑓: 0.29 (64844 hom.)
• Consequence: EGFR ENST00000275493.7 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.36

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 7-55153962-G-A is Benign according to our data. Variant chr7-55153962-G-A is described in ClinVar as [Benign]. Clinvar id is 1248590.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.632 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EGFR	NM_005228.5	c.748-49G>A		intron_variant		ENST00000275493.7	NP_005219.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EGFR	ENST00000275493.7	c.748-49G>A		intron_variant		1	NM_005228.5	ENSP00000275493	P1

Frequencies

GnomAD3 genomes AF: 0.246 AC: 37334 AN: 151902 Hom.: 5609 Cov.: 32

Gnomad AFR AF: 0.0977

Gnomad AMI AF: 0.300

Gnomad AMR AF: 0.330

Gnomad ASJ AF: 0.225

Gnomad EAS AF: 0.651

Gnomad SAS AF: 0.345

Gnomad FIN AF: 0.274

Gnomad MID AF: 0.297

Gnomad NFE AF: 0.274

Gnomad OTH AF: 0.273

GnomAD3 exomes AF: 0.306 AC: 76900 AN: 251088 Hom.: 13405 AF XY: 0.310 AC XY: 42093 AN XY: 135742

Gnomad AFR exome AF: 0.0961

Gnomad AMR exome AF: 0.352

Gnomad ASJ exome AF: 0.231

Gnomad EAS exome AF: 0.635

Gnomad SAS exome AF: 0.336

Gnomad FIN exome AF: 0.275

Gnomad NFE exome AF: 0.273

Gnomad OTH exome AF: 0.307

GnomAD4 exome AF: 0.287 AC: 420028 AN: 1461426 Hom.: 64844 Cov.: 34 AF XY: 0.289 AC XY: 209944 AN XY: 727038

Gnomad4 AFR exome AF: 0.0901

Gnomad4 AMR exome AF: 0.345

Gnomad4 ASJ exome AF: 0.224

Gnomad4 EAS exome AF: 0.670

Gnomad4 SAS exome AF: 0.335

Gnomad4 FIN exome AF: 0.278

Gnomad4 NFE exome AF: 0.276

Gnomad4 OTH exome AF: 0.289

GnomAD4 genome AF: 0.246 AC: 37325 AN: 152020 Hom.: 5602 Cov.: 32 AF XY: 0.253 AC XY: 18777 AN XY: 74306

Gnomad4 AFR AF: 0.0976

Gnomad4 AMR AF: 0.330

Gnomad4 ASJ AF: 0.225

Gnomad4 EAS AF: 0.650

Gnomad4 SAS AF: 0.346

Gnomad4 FIN AF: 0.274

Gnomad4 NFE AF: 0.274

Gnomad4 OTH AF: 0.272

Alfa AF: 0.268 Hom.: 4288

Bravo AF: 0.245

Asia WGS AF: 0.460 AC: 1596 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 10, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.0050
DANN	Benign	0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

Other links and lift over

dbSNP: rs4947986; hg19: chr7-55221655; COSMIC: COSV51773953;