Genetic Variant NM_006164.5:c.236A>T (chr2-177234081-T-A) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1PM2PM5

The NM_006164.5(NFE2L2):c.236A>T(p.Glu79Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E79K) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Consequence

NFE2L2
NM_006164.5 missense

Scores

Clinical Significance

Likely pathogenic no assertion criteria provided P:6

Conservation

PhyloP100: 7.67

Publications

15 publications found

Variant links:

Genes affected

NFE2L2 (HGNC:7782): (NFE2 like bZIP transcription factor 2) This gene encodes a transcription factor which is a member of a small family of basic leucine zipper (bZIP) proteins. The encoded transcription factor regulates genes which contain antioxidant response elements (ARE) in their promoters; many of these genes encode proteins involved in response to injury and inflammation which includes the production of free radicals. Multiple transcript variants encoding different isoforms have been characterized for this gene. [provided by RefSeq, Sep 2015]

NFE2L2 Gene-Disease associations (from GenCC):

immunodeficiency, developmental delay, and hypohomocysteinemia
Inheritance: AD Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Illumina, G2P

NFE2L2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_006164.5

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr2-177234082-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 376466.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NFE2L2	NM_006164.5 link	c.236A>T	p.Glu79Val	missense_variant	Exon 2 of 5	ENST00000397062.8	NP_006155.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NFE2L2	ENST00000397062.8 link	c.236A>T	p.Glu79Val	missense_variant	Exon 2 of 5	1	NM_006164.5	ENSP00000380252.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:6

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Squamous cell lung carcinoma

Pathogenic:1

May 31, 2016

Database of Curated Mutations (DoCM)

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Lung adenocarcinoma

Pathogenic:1

May 31, 2016

Database of Curated Mutations (DoCM)

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Neoplasm of uterine cervix

Pathogenic:1

May 31, 2016

Database of Curated Mutations (DoCM)

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Transitional cell carcinoma of the bladder

Pathogenic:1

May 31, 2016

Database of Curated Mutations (DoCM)

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Hepatocellular carcinoma

Pathogenic:1

May 31, 2016

Database of Curated Mutations (DoCM)

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Squamous cell carcinoma of the head and neck

Pathogenic:1

May 31, 2016

Database of Curated Mutations (DoCM)

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.87

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Uncertain

0.010

CADD

Pathogenic

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.51

.;D;.;.;.;T;T;.;.;.

Eigen

Pathogenic

0.87

Eigen_PC

Pathogenic

0.83

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.92

.;D;D;D;D;D;D;D;D;D

M_CAP

Uncertain

0.14

MetaRNN

Uncertain

0.56

D;D;D;D;D;D;D;D;D;D

MetaSVM

Benign

-0.51

MutationAssessor

Pathogenic

3.1

.;M;.;.;.;.;.;.;.;.

PhyloP100

7.7

PrimateAI

Uncertain

0.70

PROVEAN

Pathogenic

-4.7

D;D;D;.;N;D;.;D;D;.

REVEL

Uncertain

0.53

Sift

Pathogenic

0.0

D;D;D;.;D;D;.;D;D;.

Sift4G

Pathogenic

0.0

D;D;D;D;.;.;D;.;D;.

Polyphen

1.0

.;D;.;.;.;.;.;.;D;.

Vest4

0.71

MutPred

0.31

.;Loss of disorder (P = 0.0362);.;.;.;.;.;.;.;.;

MVP

0.61

MPC

0.70

ClinPred

1.0

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.96

gMVP

0.57

Mutation Taster

=16/84

disease causing (ClinVar)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over