rs17290699

Variant names:

• chr7-55201204-A-C
• rs17290699
• NM_005228.5:c.2963A>C

Your query was ambiguous. Multiple possible variants found:

• chr7-55201204-A-C
• chr7-55201204-A-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005228.5(EGFR):​c.2963A>C​(p.His988Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00139 in 1,614,186 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H988Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0070 (13 hom., cov: 32)
  • Exomes 𝑓: 0.00081 (11 hom.)
• Consequence: EGFR NM_005228.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8 O:1
• Conservation: PhyloP100: 5.87
• Publications: 22 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00799039).
• BP6: Variant 7-55201204-A-C is Benign according to our data. Variant chr7-55201204-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 134029.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.007 (1066/152292) while in subpopulation AFR AF = 0.0249 (1034/41544). AF 95% confidence interval is 0.0236. There are 13 homozygotes in GnomAd4. There are 492 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 13 AD,AR gene

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.2963A>C	p.His988Pro	missense	Exon 25 of 28	NP_005219.2
	EGFR	NM_001346899.2		c.2828A>C	p.His943Pro	missense	Exon 24 of 27	NP_001333828.1
	EGFR	NM_001346900.2		c.2804A>C	p.His935Pro	missense	Exon 25 of 28	NP_001333829.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EGFR	ENST00000275493.7	TSL:1 MANE Select	c.2963A>C	p.His988Pro	missense	Exon 25 of 28	ENSP00000275493.2
	EGFR	ENST00000455089.5	TSL:1	c.2828A>C	p.His943Pro	missense	Exon 24 of 26	ENSP00000415559.1
	EGFR	ENST00000898199.1		c.2954A>C	p.His985Pro	missense	Exon 25 of 28	ENSP00000568258.1

Frequencies

GnomAD3 genomes AF: 0.00697 AC: 1060 AN: 152174 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.0248

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

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: 0.0000882

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00174 AC: 437 AN: 251488 AF XY: 0.00131

Gnomad AFR exome AF: 0.0247

Gnomad AMR exome AF: 0.000809

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000809 AC: 1183 AN: 1461894 Hom.: 11 Cov.: 31 AF XY: 0.000689 AC XY: 501 AN XY: 727248

African (AFR) AF: 0.0298 AC: 997 AN: 33480

American (AMR) AF: 0.00112 AC: 50 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00121 AC: 7 AN: 5768

European-Non Finnish (NFE) AF: 0.0000351 AC: 39 AN: 1112012

Other (OTH) AF: 0.00139 AC: 84 AN: 60396

GnomAD4 genome AF: 0.00700 AC: 1066 AN: 152292 Hom.: 13 Cov.: 32 AF XY: 0.00661 AC XY: 492 AN XY: 74482

African (AFR) AF: 0.0249 AC: 1034 AN: 41544

American (AMR) AF: 0.00131 AC: 20 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68034

Other (OTH) AF: 0.00284 AC: 6 AN: 2112

Alfa AF: 0.00280 Hom.: 8

Bravo AF: 0.00795

ESP6500AA AF: 0.0261 AC: 115

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00221 AC: 268

Asia WGS AF: 0.00346 AC: 12 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	Hereditary cancer-predisposing syndrome (2)
-	-	1	EGFR-related lung cancer (1)
-	-	1	Lung cancer (1)
-	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	23
DANN	Benign	0.95
DEOGEN2	Benign	0.30	T
Eigen	Benign	0.13
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.0080	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		5.9
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.16
Sift	Benign	0.25	T
Sift4G	Benign	0.30	T
Polyphen		0.0	B
Vest4		0.58
MVP		0.57
MPC		0.22
ClinPred		0.035	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.75
gMVP		0.79
Mutation Taster		=82/18	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs17290699; hg19: chr7-55268897;