rs587778249

Variant names:

• chr7-55161570-G-A
• rs587778249
• NM_005228.5:c.1570G>A

Your query was ambiguous. Multiple possible variants found:

• chr7-55161570-G-A
• chr7-55161570-G-C

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_005228.5(EGFR):​c.1570G>A​(p.Val524Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000173 in 1,614,160 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V524L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: EGFR NM_005228.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3 O:1
• Conservation: PhyloP100: 1.23
• Publications: 9 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: G2P, Ambry Genetics, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• neonatal inflammatory skin and bowel disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.13428235).
• BP6: Variant 7-55161570-G-A is Benign according to our data. Variant chr7-55161570-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 134022.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005228.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EGFR	NM_005228.5	MANE Select	c.1570G>A	p.Val524Ile	missense	Exon 13 of 28	NP_005219.2
	EGFR	NM_001346899.2		c.1435G>A	p.Val479Ile	missense	Exon 12 of 27	NP_001333828.1
	EGFR	NM_001346900.2		c.1411G>A	p.Val471Ile	missense	Exon 13 of 28	NP_001333829.1	C9JYS6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EGFR	ENST00000275493.7	TSL:1 MANE Select	c.1570G>A	p.Val524Ile	missense	Exon 13 of 28	ENSP00000275493.2	P00533-1
	EGFR	ENST00000455089.5	TSL:1	c.1435G>A	p.Val479Ile	missense	Exon 12 of 26	ENSP00000415559.1	Q504U8
	EGFR	ENST00000344576.7	TSL:1	c.1570G>A	p.Val524Ile	missense	Exon 13 of 16	ENSP00000345973.2	P00533-3

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152270 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000239 AC: 6 AN: 251482 AF XY: 0.0000368

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000178 AC: 26 AN: 1461890 Hom.: 0 Cov.: 32 AF XY: 0.0000179 AC XY: 13 AN XY: 727246

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.0000671 AC: 3 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000171 AC: 19 AN: 1112012

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152270 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74396

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41468

American (AMR) AF: 0.000131 AC: 2 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5206

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68044

Other (OTH) AF: 0.00 AC: 0 AN: 2094

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	EGFR-related lung cancer (1)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	1	-	not provided (1)
-	-	1	not specified (2)
-	-	1	Ovarian cancer (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	13
DANN	Uncertain	0.99
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.16
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.90	L
PhyloP100		1.2
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.12	N
REVEL	Benign	0.034
Sift	Benign	0.053	T
Sift4G	Benign	0.14	T
Polyphen		0.037	B
Vest4		0.041
MutPred		0.37		Gain of catalytic residue at V524 (P = 0.16)
MVP		0.57
MPC		0.42
ClinPred		0.064	T
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.24
gMVP		0.51
Mutation Taster		=81/19	polymorphism

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

Other links and lift over

dbSNP: rs587778249; hg19: chr7-55229263; COSMIC: COSV51826432;