Variant 2-177234082-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PS1_ModeratePM1PM2PM5PP5

The ENST00000397062.8(NFE2L2):c.235G>A(p.Glu79Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E79D) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

Consequence

NFE2L2
ENST00000397062.8 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 7.57

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 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PS1

Transcript ENST00000397062.8 (NFE2L2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt

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 ENST00000397062.8

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr2-177234080-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 376468.Status of the report is no_assertion_criteria_provided, 0 stars.

PP5

Variant 2-177234082-C-T is Pathogenic according to our data. Variant chr2-177234082-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 376466.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NFE2L2	NM_006164.5 linkuse as main transcript	c.235G>A	p.Glu79Lys	missense_variant	2/5	ENST00000397062.8	NP_006155.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NFE2L2	ENST00000397062.8 linkuse as main transcript	c.235G>A	p.Glu79Lys	missense_variant	2/5	1	NM_006164.5	ENSP00000380252	A1	Q16236-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Immunodeficiency, developmental delay, and hypohomocysteinemia

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 28, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.83

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.14

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.40

.;T;.;.;.;T;T;.;.;.

Eigen

Pathogenic

0.92

Eigen_PC

Pathogenic

0.89

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

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

M_CAP

Benign

0.041

MetaRNN

Uncertain

0.57

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

MetaSVM

Benign

-0.53

MutationAssessor

Pathogenic

3.1

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

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Uncertain

0.78

PROVEAN

Uncertain

-2.6

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

REVEL

Uncertain

0.36

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0

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

Polyphen

1.0

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

Vest4

0.76

MutPred

0.39

.;Gain of ubiquitination at E79 (P = 0.0042);.;.;.;.;.;.;.;.;

MVP

0.63

MPC

0.69

ClinPred

0.99

GERP RS

5.8

Varity_R

0.97

gMVP

0.57

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores 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

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over