7-55198724-T-C

Variant names:

• chr7-55198724-T-C
• rs1140475
• NM_005228.5:c.2709T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_005228.5(EGFR):​c.2709T>C​(p.Thr903Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.881 in 1,614,112 control chromosomes in the GnomAD database, including 626,480 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T903T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.90 (61269 hom., cov: 33)
  • Exomes 𝑓: 0.88 (565211 hom.)
• Consequence: EGFR NM_005228.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -3.10
• Publications: 70 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-AS1 (HGNC:40207): (EGFR antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 7-55198724-T-C is Benign according to our data. Variant chr7-55198724-T-C is described in ClinVar as Benign. ClinVar VariationId is 1166017.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.1 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.918 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EGFR	NM_005228.5	MANE Select	c.2709T>C	p.Thr903Thr	synonymous	Exon 23 of 28	NP_005219.2
	EGFR	NM_001346899.2		c.2574T>C	p.Thr858Thr	synonymous	Exon 22 of 27	NP_001333828.1
	EGFR	NM_001346900.2		c.2550T>C	p.Thr850Thr	synonymous	Exon 23 of 28	NP_001333829.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EGFR	ENST00000275493.7	TSL:1 MANE Select	c.2709T>C	p.Thr903Thr	synonymous	Exon 23 of 28	ENSP00000275493.2
	EGFR	ENST00000455089.5	TSL:1	c.2574T>C	p.Thr858Thr	synonymous	Exon 22 of 26	ENSP00000415559.1
	EGFR	ENST00000450046.2	TSL:4	c.2550T>C	p.Thr850Thr	synonymous	Exon 23 of 28	ENSP00000413354.2

Frequencies

GnomAD3 genomes AF: 0.897 AC: 136403 AN: 152142 Hom.: 61216 Cov.: 33

Gnomad AFR AF: 0.926

Gnomad AMI AF: 0.913

Gnomad AMR AF: 0.898

Gnomad ASJ AF: 0.892

Gnomad EAS AF: 0.933

Gnomad SAS AF: 0.937

Gnomad FIN AF: 0.884

Gnomad MID AF: 0.908

Gnomad NFE AF: 0.875

Gnomad OTH AF: 0.891

GnomAD2 exomes AF: 0.895 AC: 224962 AN: 251476 AF XY: 0.897

Gnomad AFR exome AF: 0.925

Gnomad AMR exome AF: 0.892

Gnomad ASJ exome AF: 0.899

Gnomad EAS exome AF: 0.925

Gnomad FIN exome AF: 0.887

Gnomad NFE exome AF: 0.875

Gnomad OTH exome AF: 0.897

GnomAD4 exome AF: 0.879 AC: 1284879 AN: 1461852 Hom.: 565211 Cov.: 72 AF XY: 0.881 AC XY: 640613 AN XY: 727228

African (AFR) AF: 0.929 AC: 31103 AN: 33480

American (AMR) AF: 0.893 AC: 39957 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.900 AC: 23510 AN: 26136

East Asian (EAS) AF: 0.938 AC: 37246 AN: 39700

South Asian (SAS) AF: 0.937 AC: 80783 AN: 86258

European-Finnish (FIN) AF: 0.884 AC: 47225 AN: 53406

Middle Eastern (MID) AF: 0.920 AC: 5305 AN: 5768

European-Non Finnish (NFE) AF: 0.869 AC: 966416 AN: 1111984

Other (OTH) AF: 0.883 AC: 53334 AN: 60396

GnomAD4 genome AF: 0.897 AC: 136514 AN: 152260 Hom.: 61269 Cov.: 33 AF XY: 0.899 AC XY: 66918 AN XY: 74434

African (AFR) AF: 0.926 AC: 38474 AN: 41546

American (AMR) AF: 0.898 AC: 13741 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.892 AC: 3097 AN: 3472

East Asian (EAS) AF: 0.933 AC: 4827 AN: 5176

South Asian (SAS) AF: 0.937 AC: 4520 AN: 4824

European-Finnish (FIN) AF: 0.884 AC: 9379 AN: 10606

Middle Eastern (MID) AF: 0.908 AC: 267 AN: 294

European-Non Finnish (NFE) AF: 0.875 AC: 59490 AN: 68018

Other (OTH) AF: 0.891 AC: 1886 AN: 2116

Alfa AF: 0.884 Hom.: 115080

Bravo AF: 0.899

Asia WGS AF: 0.930 AC: 3236 AN: 3478

EpiCase AF: 0.890

EpiControl AF: 0.880

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	EGFR-related lung cancer (1)
-	-	1	Inflammatory skin and bowel disease, neonatal, 2 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.049
DANN	Benign	0.49
PhyloP100		-3.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs1140475; hg19: chr7-55266417; COSMIC: COSV51770428;