NM_006164.5:c.239C>A

Variant names:

• chr2-177234078-G-T
• rs1553487947
• NM_006164.5:c.239C>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PP5_Moderate

The NM_006164.5(NFE2L2):​c.239C>A​(p.Thr80Lys) 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 Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: NFE2L2 NM_006164.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.60
• Publications: 7 publications found

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

ACMG classification

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, 6 uncertain in NM_006164.5
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-177234078-G-T is Pathogenic according to our data. Variant chr2-177234078-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 445148.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NFE2L2	NM_006164.5	c.239C>A	p.Thr80Lys	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	c.239C>A	p.Thr80Lys	missense_variant	Exon 2 of 5	1	NM_006164.5	ENSP00000380252.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Immunodeficiency, developmental delay, and hypohomocysteinemia Pathogenic:1

Oct 30, 2017

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

Apr 21, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects NFE2L2 function (PMID: 24130096, 29018201, 31107239). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 445148). This missense change has been observed in individual(s) with NFE2L2-related conditions (PMID: 29018201). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with lysine, which is basic and polar, at codon 80 of the NFE2L2 protein (p.Thr80Lys). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.59	.;D;.;.;.;T;T;.;.;.
Eigen	Pathogenic	0.98
Eigen_PC	Pathogenic	0.95
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.92	.;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.058	D
MetaRNN	Uncertain	0.63	D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.52	T
MutationAssessor	Pathogenic	3.1	.;M;.;.;.;.;.;.;.;.
PhyloP100		9.6
PrimateAI	Uncertain	0.75	T
PROVEAN	Uncertain	-4.0	D;D;D;.;N;D;.;D;D;.
REVEL	Uncertain	0.54
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		0.34		.;Gain of ubiquitination at T80 (P = 0.0077);.;.;.;.;.;.;.;.;
MVP		0.55
MPC		0.72
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.94
gMVP		0.74
Mutation Taster		=2/98	disease causing (ClinVar)

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: rs1553487947; hg19: chr2-178098806; COSMIC: COSV67960020; COSMIC: COSV67960020;