chr7-55019284-C-T

Variant names:

• chr7-55019284-C-T
• rs773069229
• NM_005228.5:c.7C>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_005228.5(EGFR):​c.7C>T​(p.Pro3Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000266 in 1,504,142 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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. P3L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: EGFR NM_005228.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.0200
• Publications: 7 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 -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21756393).
• BP6: Variant 7-55019284-C-T is Benign according to our data. Variant chr7-55019284-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 1352648.

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.7C>T	p.Pro3Ser	missense	Exon 1 of 28	NP_005219.2
	EGFR	NM_001346899.2		c.7C>T	p.Pro3Ser	missense	Exon 1 of 27	NP_001333828.1
	EGFR	NM_001346898.2		c.7C>T	p.Pro3Ser	missense	Exon 1 of 27	NP_001333827.1	E7BSV0

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EGFR	ENST00000275493.7	TSL:1 MANE Select	c.7C>T	p.Pro3Ser	missense	Exon 1 of 28	ENSP00000275493.2	P00533-1
	EGFR	ENST00000455089.5	TSL:1	c.7C>T	p.Pro3Ser	missense	Exon 1 of 26	ENSP00000415559.1	Q504U8
	EGFR	ENST00000344576.7	TSL:1	c.7C>T	p.Pro3Ser	missense	Exon 1 of 16	ENSP00000345973.2	P00533-3

Frequencies

GnomAD3 genomes AF: 0.00000662 AC: 1 AN: 151148 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000148

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000222 AC: 3 AN: 1352994 Hom.: 0 Cov.: 30 AF XY: 0.00000149 AC XY: 1 AN XY: 670830

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

African (AFR) AF: 0.00 AC: 0 AN: 27820

American (AMR) AF: 0.00 AC: 0 AN: 35464

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22822

East Asian (EAS) AF: 0.00 AC: 0 AN: 30200

South Asian (SAS) AF: 0.00 AC: 0 AN: 77440

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46154

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5014

European-Non Finnish (NFE) AF: 0.00000285 AC: 3 AN: 1053634

Other (OTH) AF: 0.00 AC: 0 AN: 54446

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000662 AC: 1 AN: 151148 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 73784

African (AFR) AF: 0.00 AC: 0 AN: 41344

American (AMR) AF: 0.00 AC: 0 AN: 15180

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10182

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67674

Other (OTH) AF: 0.00 AC: 0 AN: 2080

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.66	T
M_CAP	Pathogenic	0.96	D
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	0.69	N
PhyloP100		-0.020
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-0.030	N
REVEL	Benign	0.18
Sift	Benign	0.052	T
Sift4G	Benign	0.20	T
Polyphen		0.099	B
Vest4		0.15
MutPred		0.18		Gain of phosphorylation at P3 (P = 0.0245)
MVP		0.71
MPC		0.52
ClinPred		0.14	T
GERP RS		2.3
PromoterAI		0.065	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.027
gMVP		0.51
Mutation Taster		=63/37	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: rs773069229; hg19: chr7-55086977;