rs2227984

Positions:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_005228.5(EGFR):c.1887T>A(p.Thr629Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.352 in 1,613,896 control chromosomes in the GnomAD database, including 103,078 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.34 ( 9180 hom., cov: 33)

Exomes 𝑓: 0.35 ( 93898 hom. )

Consequence

EGFR
NM_005228.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.663

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 7-55171181-T-A is Benign according to our data. Variant chr7-55171181-T-A is described in ClinVar as [Benign]. Clinvar id is 259677.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-55171181-T-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.663 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.536 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EGFR	NM_005228.5 linkuse as main transcript	c.1887T>A	p.Thr629Thr	synonymous_variant	16/28	ENST00000275493.7	NP_005219.2	P00533-1Q504U8F2YGG7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
EGFR	ENST00000275493.7 linkuse as main transcript	c.1887T>A	p.Thr629Thr	synonymous_variant	16/28	1	NM_005228.5	ENSP00000275493.2	P00533-1
EGFR	ENST00000455089.5 linkuse as main transcript	c.1752T>A	p.Thr584Thr	synonymous_variant	15/26	1		ENSP00000415559.1	Q504U8
EGFR	ENST00000450046.2 linkuse as main transcript	c.1728T>A	p.Thr576Thr	synonymous_variant	16/28	4		ENSP00000413354.2	C9JYS6
EGFR	ENST00000700145.1 linkuse as main transcript	c.234T>A	p.Thr78Thr	synonymous_variant	3/9			ENSP00000514824.1	A0A8V8TPW8

Frequencies

GnomAD3 genomes

AF:

0.341

AC:

51789

AN:

152040

Hom.:

9181

Cov.:

show subpopulations

Gnomad AFR

AF:

0.281

Gnomad AMI

AF:

0.343

Gnomad AMR

AF:

0.367

Gnomad ASJ

AF:

0.478

Gnomad EAS

AF:

0.552

Gnomad SAS

AF:

0.440

Gnomad FIN

AF:

0.331

Gnomad MID

AF:

0.446

Gnomad NFE

AF:

0.341

Gnomad OTH

AF:

0.367

GnomAD3 exomes

AF:

0.376

AC:

94569

AN:

251376

Hom.:

18426

AF XY:

0.380

AC XY:

51581

AN XY:

135860

show subpopulations

Gnomad AFR exome

AF:

0.279

Gnomad AMR exome

AF:

0.394

Gnomad ASJ exome

AF:

0.483

Gnomad EAS exome

AF:

0.539

Gnomad SAS exome

AF:

0.423

Gnomad FIN exome

AF:

0.329

Gnomad NFE exome

AF:

0.344

Gnomad OTH exome

AF:

0.394

GnomAD4 exome

AF:

0.353

AC:

516104

AN:

1461738

Hom.:

93898

Cov.:

AF XY:

0.356

AC XY:

258718

AN XY:

727188

show subpopulations

Gnomad4 AFR exome

AF:

0.278

Gnomad4 AMR exome

AF:

0.393

Gnomad4 ASJ exome

AF:

0.487

Gnomad4 EAS exome

AF:

0.603

Gnomad4 SAS exome

AF:

0.424

Gnomad4 FIN exome

AF:

0.328

Gnomad4 NFE exome

AF:

0.335

Gnomad4 OTH exome

AF:

0.379

GnomAD4 genome

AF:

0.340

AC:

51801

AN:

152158

Hom.:

9180

Cov.:

AF XY:

0.345

AC XY:

25637

AN XY:

74380

show subpopulations

Gnomad4 AFR

AF:

0.280

Gnomad4 AMR

AF:

0.366

Gnomad4 ASJ

AF:

0.478

Gnomad4 EAS

AF:

0.553

Gnomad4 SAS

AF:

0.440

Gnomad4 FIN

AF:

0.331

Gnomad4 NFE

AF:

0.341

Gnomad4 OTH

AF:

0.368

Alfa

AF:

0.358

Hom.:

3333

Bravo

AF:

0.345

Asia WGS

AF:

0.480

AC:

1668

AN:

3478

EpiCase

AF:

0.364

EpiControl

AF:

0.360

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 07, 2019	- -

EGFR-related lung cancer

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Lung cancer

Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Hereditary cancer-predisposing syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 18, 2024

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Inflammatory skin and bowel disease, neonatal, 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

0.22

DANN

Benign

0.73

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over