rs121434568

chr7-55191822-T-Achr7-55191822-T-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2_SupportingPM5PP3_StrongPP5

The NM_005228(EGFR):c.2573T>A(p.Leu858Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD Genomes project. In-silico tool predicts a pathogenic outcome for this variant. 12/20 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L858R) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

EGFR
NM_005228 missense

Scores

Clinical Significance

Likely pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 7.96

Links

EGFR (HGNC:3236):

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_005228

PM2

Very rare variant; Number of alleles below threshold, Median coverage is 32.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr7-55191822-T-G is described in ClinVar as [drug_response]. Clinvar id is 16609. Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=2, drug_response=3}.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.988

PP5

Variant 7:55191822-T>A is Pathogenic according to our data. Variant chr7-55191822-T-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 376281. Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EGFR	NM_005228.5 linkuse as main transcript	c.2573T>A	p.Leu858Gln	missense_variant	21/28	ENST00000275493.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EGFR	ENST00000275493.7 linkuse as main transcript	c.2573T>A	p.Leu858Gln	missense_variant	21/28	1	NM_005228.5	P1	P00533-1
EGFR	ENST00000455089.5 linkuse as main transcript	c.2438T>A	p.Leu813Gln	missense_variant	20/26	1
EGFR	ENST00000450046.2 linkuse as main transcript	c.2414T>A	p.Leu805Gln	missense_variant	21/28	4
EGFR	ENST00000700145.1 linkuse as main transcript	c.899+23T>A		intron_variant

Frequencies

GnomAD3 genomes

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Non-small cell lung carcinoma

Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

Jul 14, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.50

BayesDel_noAF

Pathogenic

0.48

Cadd

Pathogenic

Dann

Uncertain

1.0

DEOGEN2

Pathogenic

0.84

D;D;D

Eigen

Pathogenic

0.98

Eigen_PC

Pathogenic

0.90

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

D;D;D

M_CAP

Pathogenic

0.72

MetaRNN

Pathogenic

0.99

D;D;D

MetaSVM

Pathogenic

1.0

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Pathogenic

0.90

PROVEAN

Pathogenic

-5.2

D;.;D

REVEL

Pathogenic

0.96

Sift

Pathogenic

0.0

D;.;D

Sift4G

Pathogenic

0.0010

D;D;D

Polyphen

1.0

D;.;D

Vest4

0.99

MutPred

0.89

.;.;Gain of disorder (P = 0.0531);

MVP

0.99

MPC

1.5

ClinPred

1.0

GERP RS

5.7

Varity_R

0.95

gMVP

0.97

Splicing

Find out SpliceAI and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Links

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over