rs41321844

Variant names:

• chr7-55205469-G-A
• rs41321844
• NM_005228.5:c.3485G>A

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.3485G>A​(p.Ser1162Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00064 in 1,614,152 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict 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. S1162R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0034 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00035 (2 hom.)
• Consequence: EGFR NM_005228.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4 O:1
• Conservation: PhyloP100: -0.150
• Publications: 12 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=0.004688412).
• BP6: Variant 7-55205469-G-A is Benign according to our data. Variant chr7-55205469-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 134031.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 = 0.0034 (517/152268) while in subpopulation AFR AF = 0.012 (498/41556). AF 95% confidence interval is 0.0111. There are 4 homozygotes in GnomAd4. There are 259 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 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.3485G>A	p.Ser1162Asn	missense	Exon 28 of 28	NP_005219.2
	EGFR	NM_001346899.2		c.3350G>A	p.Ser1117Asn	missense	Exon 27 of 27	NP_001333828.1
	EGFR	NM_001346900.2		c.3326G>A	p.Ser1109Asn	missense	Exon 28 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.3485G>A	p.Ser1162Asn	missense	Exon 28 of 28	ENSP00000275493.2	P00533-1
	EGFR	ENST00000898199.1		c.3476G>A	p.Ser1159Asn	missense	Exon 28 of 28	ENSP00000568258.1
	EGFR	ENST00000898202.1		c.3446G>A	p.Ser1149Asn	missense	Exon 27 of 27	ENSP00000568261.1

Frequencies

GnomAD3 genomes AF: 0.00342 AC: 520 AN: 152150 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.0121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00288

GnomAD2 exomes AF: 0.000877 AC: 220 AN: 250970 AF XY: 0.000649

Gnomad AFR exome AF: 0.0119

Gnomad AMR exome AF: 0.000608

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000353 AC: 516 AN: 1461884 Hom.: 2 Cov.: 31 AF XY: 0.000294 AC XY: 214 AN XY: 727240

African (AFR) AF: 0.0127 AC: 424 AN: 33480

American (AMR) AF: 0.000783 AC: 35 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: 0.0000812 AC: 7 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5768

European-Non Finnish (NFE) AF: 0.00000719 AC: 8 AN: 1112010

Other (OTH) AF: 0.000596 AC: 36 AN: 60396

GnomAD4 genome AF: 0.00340 AC: 517 AN: 152268 Hom.: 4 Cov.: 32 AF XY: 0.00348 AC XY: 259 AN XY: 74458

African (AFR) AF: 0.0120 AC: 498 AN: 41556

American (AMR) AF: 0.000588 AC: 9 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68016

Other (OTH) AF: 0.00285 AC: 6 AN: 2106

Alfa AF: 0.00141 Hom.: 1

Bravo AF: 0.00378

ESP6500AA AF: 0.0107 AC: 47

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000865 AC: 105

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	EGFR-related lung cancer (1)
-	-	1	Hereditary cancer-predisposing syndrome (1)
-	-	1	Lung cancer;C4015130:Inflammatory skin and bowel disease, neonatal, 2 (1)
-	-	1	not provided (1)
-	-	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	0.024
DANN	Benign	0.40
DEOGEN2	Benign	0.24	T
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.081	N
LIST_S2	Benign	0.55	T
MetaRNN	Benign	0.0047	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.22	N
PhyloP100		-0.15
PrimateAI	Benign	0.27	T
PROVEAN	Benign	0.040	N
REVEL	Benign	0.085
Sift	Benign	0.46	T
Sift4G	Benign	0.71	T
Polyphen		0.0	B
Vest4		0.038
MVP		0.51
MPC		0.068
ClinPred		0.0015	T
GERP RS		-9.5
Varity_R		0.044
gMVP		0.077
Mutation Taster		=99/1	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: rs41321844; hg19: chr7-55273162; COSMIC: COSV51827210;