rs17290005

Positions:

• chr7-55160157-A-G
• chr7-55160157-A-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_005228.5(EGFR):​c.1317A>G​(p.Ala439Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00158 in 1,614,190 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0082 (23 hom., cov: 33)
  • Exomes 𝑓: 0.00089 (25 hom.)
• Consequence: EGFR NM_005228.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -2.05

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 7-55160157-A-G is Benign according to our data. Variant chr7-55160157-A-G is described in ClinVar as [Benign]. Clinvar id is 782267.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.05 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00816 (1243/152354) while in subpopulation AFR AF= 0.028 (1163/41582). AF 95% confidence interval is 0.0266. There are 23 homozygotes in gnomad4. There are 607 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 23 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EGFR	NM_005228.5	c.1317A>G	p.Ala439Ala	synonymous_variant	12/28	ENST00000275493.7	NP_005219.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EGFR	ENST00000275493.7	c.1317A>G	p.Ala439Ala	synonymous_variant	12/28	1	NM_005228.5	ENSP00000275493.2

Frequencies

GnomAD3 genomes AF: 0.00812 AC: 1236 AN: 152236 Hom.: 23 Cov.: 33

Gnomad AFR AF: 0.0279

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00360

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00200 AC: 504 AN: 251434 Hom.: 8 AF XY: 0.00158 AC XY: 215 AN XY: 135896

Gnomad AFR exome AF: 0.0266

Gnomad AMR exome AF: 0.00142

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000132

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.000891 AC: 1303 AN: 1461836 Hom.: 25 Cov.: 31 AF XY: 0.000730 AC XY: 531 AN XY: 727222

Gnomad4 AFR exome AF: 0.0295

Gnomad4 AMR exome AF: 0.00161

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000935

Gnomad4 OTH exome AF: 0.00214

GnomAD4 genome AF: 0.00816 AC: 1243 AN: 152354 Hom.: 23 Cov.: 33 AF XY: 0.00815 AC XY: 607 AN XY: 74506

Gnomad4 AFR AF: 0.0280

Gnomad4 AMR AF: 0.00359

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00417 Hom.: 4

Bravo AF: 0.00950

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

May 12, 2022

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

EGFR-related lung cancer Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Hereditary cancer-predisposing syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 09, 2024

This alteration is classified as likely 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.26
DANN	Benign	0.43

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

Publications

LitVar

Other links and lift over

dbSNP: rs17290005; hg19: chr7-55227850; COSMIC: COSV104369090; COSMIC: COSV104369090;