rs4947986

Variant names:

• chr7-55153962-G-A
• rs4947986
• NM_005228.5:c.748-49G>A

Your query was ambiguous. Multiple possible variants found:

• chr7-55153962-G-A
• chr7-55153962-G-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.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 NM_005228.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.36
• Publications: 28 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=-0.85).
• BP6: Variant 7-55153962-G-A is Benign according to our data. Variant chr7-55153962-G-A is described in ClinVar as Benign. ClinVar VariationId 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 rank	MANE	Protein	UniProt
EGFR	NM_005228.5	c.748-49G>A		intron_variant	Intron 6 of 27	ENST00000275493.7	NP_005219.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EGFR	ENST00000275493.7	c.748-49G>A		intron_variant	Intron 6 of 27	1	NM_005228.5	ENSP00000275493.2

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

GnomAD2 exomes AF: 0.306 AC: 76900 AN: 251088 AF XY: 0.310

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 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

African (AFR) AF: 0.0901 AC: 3016 AN: 33468

American (AMR) AF: 0.345 AC: 15436 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.224 AC: 5863 AN: 26130

East Asian (EAS) AF: 0.670 AC: 26597 AN: 39694

South Asian (SAS) AF: 0.335 AC: 28925 AN: 86250

European-Finnish (FIN) AF: 0.278 AC: 14865 AN: 53378

Middle Eastern (MID) AF: 0.255 AC: 1468 AN: 5768

European-Non Finnish (NFE) AF: 0.276 AC: 306388 AN: 1111644

Other (OTH) AF: 0.289 AC: 17470 AN: 60380

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

African (AFR) AF: 0.0976 AC: 4050 AN: 41482

American (AMR) AF: 0.330 AC: 5036 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.225 AC: 780 AN: 3472

East Asian (EAS) AF: 0.650 AC: 3336 AN: 5130

South Asian (SAS) AF: 0.346 AC: 1663 AN: 4808

European-Finnish (FIN) AF: 0.274 AC: 2898 AN: 10560

Middle Eastern (MID) AF: 0.293 AC: 86 AN: 294

European-Non Finnish (NFE) AF: 0.274 AC: 18628 AN: 67970

Other (OTH) AF: 0.272 AC: 574 AN: 2110

Alfa AF: 0.270 Hom.: 5797

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

Jan 10, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.0050
DANN	Benign	0.87
PhyloP100		-1.4
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4947986; hg19: chr7-55221655;