chr7-55019297-C-A

Position:

• chr7-55019297-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005228.5(EGFR):​c.20C>A​(p.Ala7Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000294 in 1,360,766 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A7P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: EGFR NM_005228.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.40

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25728753).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EGFR	NM_005228.5	c.20C>A	p.Ala7Asp	missense_variant	1/28	ENST00000275493.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EGFR	ENST00000275493.7	c.20C>A	p.Ala7Asp	missense_variant	1/28	1	NM_005228.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000294 AC: 4 AN: 1360766 Hom.: 0 Cov.: 30 AF XY: 0.00000148 AC XY: 1 AN XY: 675100

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000284

Gnomad4 OTH exome AF: 0.0000182

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

EGFR-related lung cancer Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Apr 26, 2021

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with EGFR-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces alanine with aspartic acid at codon 7 of the EGFR protein (p.Ala7Asp). The alanine residue is weakly conserved and there is a moderate physicochemical difference between alanine and aspartic acid. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.35
BayesDel_addAF	Benign	-0.046	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	4.7
DANN	Benign	0.94
DEOGEN2	Benign	0.25	T;.;T;.;.;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.057	N
LIST_S2	Benign	0.68	T;T;T;T;T;T
M_CAP	Pathogenic	0.92	D
MetaRNN	Benign	0.26	T;T;T;T;T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	1.2	.;L;.;L;L;L
MutationTaster	Benign	1.0	N;N;N;N;N;N
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-0.54	N;N;.;N;N;N
REVEL	Benign	0.23
Sift	Uncertain	0.028	D;T;.;D;T;T
Sift4G	Benign	0.53	T;T;T;T;T;T
Polyphen		0.037	B;B;.;B;B;B
Vest4		0.27
MutPred		0.27		Loss of methylation at R2 (P = 0.0454);Loss of methylation at R2 (P = 0.0454);Loss of methylation at R2 (P = 0.0454);Loss of methylation at R2 (P = 0.0454);Loss of methylation at R2 (P = 0.0454);Loss of methylation at R2 (P = 0.0454);
MVP		0.81
MPC		0.81
ClinPred		0.11	T
GERP RS		0.0053
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.13
gMVP		0.71

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: rs1786367350; hg19: chr7-55086990;