7-55171181-T-A

Variant names:

• chr7-55171181-T-A
• rs2227984
• NM_005228.5:c.1887T>A

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.1887T>A​(p.Thr629Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.352 in 1,613,896 control chromosomes in the GnomAD database, including 103,078 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. T629T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.34 (9180 hom., cov: 33)
  • Exomes 𝑓: 0.35 (93898 hom.)
• Consequence: EGFR NM_005228.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.663
• Publications: 53 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 7-55171181-T-A is Benign according to our data. Variant chr7-55171181-T-A is described in ClinVar as Benign. ClinVar VariationId is 259677.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.663 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.536 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EGFR	NM_005228.5	MANE Select	c.1887T>A	p.Thr629Thr	synonymous	Exon 16 of 28	NP_005219.2
	EGFR	NM_001346899.2		c.1752T>A	p.Thr584Thr	synonymous	Exon 15 of 27	NP_001333828.1
	EGFR	NM_001346900.2		c.1728T>A	p.Thr576Thr	synonymous	Exon 16 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.1887T>A	p.Thr629Thr	synonymous	Exon 16 of 28	ENSP00000275493.2	P00533-1
	EGFR	ENST00000455089.5	TSL:1	c.1752T>A	p.Thr584Thr	synonymous	Exon 15 of 26	ENSP00000415559.1	Q504U8
	EGFR	ENST00000898199.1		c.1878T>A	p.Thr626Thr	synonymous	Exon 16 of 28	ENSP00000568258.1

Frequencies

GnomAD3 genomes AF: 0.341 AC: 51789 AN: 152040 Hom.: 9181 Cov.: 33

Gnomad AFR AF: 0.281

Gnomad AMI AF: 0.343

Gnomad AMR AF: 0.367

Gnomad ASJ AF: 0.478

Gnomad EAS AF: 0.552

Gnomad SAS AF: 0.440

Gnomad FIN AF: 0.331

Gnomad MID AF: 0.446

Gnomad NFE AF: 0.341

Gnomad OTH AF: 0.367

GnomAD2 exomes AF: 0.376 AC: 94569 AN: 251376 AF XY: 0.380

Gnomad AFR exome AF: 0.279

Gnomad AMR exome AF: 0.394

Gnomad ASJ exome AF: 0.483

Gnomad EAS exome AF: 0.539

Gnomad FIN exome AF: 0.329

Gnomad NFE exome AF: 0.344

Gnomad OTH exome AF: 0.394

GnomAD4 exome AF: 0.353 AC: 516104 AN: 1461738 Hom.: 93898 Cov.: 44 AF XY: 0.356 AC XY: 258718 AN XY: 727188

African (AFR) AF: 0.278 AC: 9311 AN: 33480

American (AMR) AF: 0.393 AC: 17560 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.487 AC: 12736 AN: 26132

East Asian (EAS) AF: 0.603 AC: 23929 AN: 39696

South Asian (SAS) AF: 0.424 AC: 36605 AN: 86252

European-Finnish (FIN) AF: 0.328 AC: 17489 AN: 53382

Middle Eastern (MID) AF: 0.465 AC: 2679 AN: 5764

European-Non Finnish (NFE) AF: 0.335 AC: 372880 AN: 1111920

Other (OTH) AF: 0.379 AC: 22915 AN: 60394

GnomAD4 genome AF: 0.340 AC: 51801 AN: 152158 Hom.: 9180 Cov.: 33 AF XY: 0.345 AC XY: 25637 AN XY: 74380

African (AFR) AF: 0.280 AC: 11637 AN: 41496

American (AMR) AF: 0.366 AC: 5607 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.478 AC: 1656 AN: 3468

East Asian (EAS) AF: 0.553 AC: 2855 AN: 5160

South Asian (SAS) AF: 0.440 AC: 2122 AN: 4826

European-Finnish (FIN) AF: 0.331 AC: 3510 AN: 10592

Middle Eastern (MID) AF: 0.452 AC: 132 AN: 292

European-Non Finnish (NFE) AF: 0.341 AC: 23191 AN: 67996

Other (OTH) AF: 0.368 AC: 778 AN: 2112

Alfa AF: 0.358 Hom.: 3333

Bravo AF: 0.345

Asia WGS AF: 0.480 AC: 1668 AN: 3478

EpiCase AF: 0.364

EpiControl AF: 0.360

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.22
DANN	Benign	0.73
PhyloP100		-0.66
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs2227984; hg19: chr7-55238874; COSMIC: COSV51770406; COSMIC: COSV51770406;