rs41420046

chr7-55191736-G-Achr7-55191736-G-C

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS1

The NM_005228.5(EGFR):c.2487G>A(p.Glu829=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000388 in 1,613,956 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0019 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00023 (1 hom.)
• Consequence: EGFR NM_005228.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.679

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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 7-55191736-G-A is Benign according to our data. Variant chr7-55191736-G-A is described in ClinVar as [Benign]. Clinvar id is 259678.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr7-55191736-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.679 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00189 (287/152226) while in subpopulation AFR AF= 0.00645 (268/41528). AF 95% confidence interval is 0.00582. There are 1 homozygotes in gnomad4. There are 146 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EGFR	NM_005228.5	c.2487G>A	p.Glu829=	synonymous_variant	21/28	ENST00000275493.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EGFR	ENST00000275493.7	c.2487G>A	p.Glu829=	synonymous_variant	21/28	1	NM_005228.5	P1
EGFR	ENST00000455089.5	c.2352G>A	p.Glu784=	synonymous_variant	20/26	1
EGFR	ENST00000450046.2	c.2328G>A	p.Glu776=	synonymous_variant	21/28	4
EGFR	ENST00000700145.1	c.837G>A	p.Glu279=	synonymous_variant	8/9

Frequencies

GnomAD3 genomes AF: 0.00188 AC: 286 AN: 152108 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00645

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000637 AC: 160 AN: 251060 Hom.: 1 AF XY: 0.000560 AC XY: 76 AN XY: 135682

Gnomad AFR exome AF: 0.00795

Gnomad AMR exome AF: 0.000607

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000232 AC: 339 AN: 1461730 Hom.: 1 Cov.: 31 AF XY: 0.000212 AC XY: 154 AN XY: 727172

Gnomad4 AFR exome AF: 0.00783

Gnomad4 AMR exome AF: 0.000581

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000171

Gnomad4 OTH exome AF: 0.000397

GnomAD4 genome AF: 0.00189 AC: 287 AN: 152226 Hom.: 1 Cov.: 32 AF XY: 0.00196 AC XY: 146 AN XY: 74414

Gnomad4 AFR AF: 0.00645

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00236

Alfa AF: 0.000602 Hom.: 0

Bravo AF: 0.00215

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

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	Quest Diagnostics Nichols Institute San Juan Capistrano	Aug 25, 2021	- -

EGFR-related lung cancer Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Hereditary cancer-predisposing syndrome Benign:1

Benign, criteria provided, single submitter

curation

Sema4, Sema4

Apr 23, 2021

- -

Lung cancer Benign:1

Benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
Cadd	Benign	3.9
Dann	Benign	0.86
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs41420046; hg19: chr7-55259429; COSMIC: COSV51796834; COSMIC: COSV51796834;