rs587778555

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_006164.5(NFE2L2):​c.1106C>T​(p.Thr369Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 33)

Consequence

NFE2L2
NM_006164.5 missense

Scores

6
13

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2O:1

Conservation

PhyloP100: 3.72
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.1408115).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NFE2L2NM_006164.5 linkc.1106C>T p.Thr369Ile missense_variant Exon 5 of 5 ENST00000397062.8 NP_006155.2 Q16236-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NFE2L2ENST00000397062.8 linkc.1106C>T p.Thr369Ile missense_variant Exon 5 of 5 1 NM_006164.5 ENSP00000380252.3 Q16236-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Uncertain:1Other:1
Dec 19, 2024
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: NFE2L2 c.1106C>T (p.Thr369Ile) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 250320 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.1106C>T in individuals affected with Immunodeficiency, Developmental Delay, And Hypohomocysteinemia and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 134902). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Sep 19, 2013
ITMI
Significance: not provided
Review Status: no classification provided
Collection Method: reference population

- -

not provided Uncertain:1
Apr 09, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces threonine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 369 of the NFE2L2 protein (p.Thr369Ile). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with NFE2L2-related conditions. ClinVar contains an entry for this variant (Variation ID: 134902). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt NFE2L2 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Benign
-0.18
T
BayesDel_noAF
Benign
-0.49
CADD
Benign
21
DANN
Uncertain
0.99
DEOGEN2
Benign
0.25
.;T;.;.;.
Eigen
Uncertain
0.24
Eigen_PC
Uncertain
0.38
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Uncertain
0.86
.;D;D;D;D
M_CAP
Benign
0.0067
T
MetaRNN
Benign
0.14
T;T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Uncertain
2.3
.;M;.;.;.
PrimateAI
Benign
0.31
T
PROVEAN
Benign
-2.2
N;N;N;.;N
REVEL
Benign
0.046
Sift
Benign
0.14
T;T;T;.;T
Sift4G
Benign
0.20
T;T;T;T;.
Polyphen
0.47
.;P;.;.;.
Vest4
0.11
MutPred
0.21
.;Loss of loop (P = 0.0603);.;.;.;
MVP
0.30
MPC
0.25
ClinPred
0.51
D
GERP RS
5.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.076
gMVP
0.20

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

Publications

LitVar

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

Other links and lift over

dbSNP: rs587778555; hg19: chr2-178096225; API