Genetic Variant NFE2L3:p.Ser134Leu (chr7-26152899-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004289.7(NFE2L3):c.401C>T(p.Ser134Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000154 in 1,296,970 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000015 ( 0 hom. )

Consequence

NFE2L3
NM_004289.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.298

Publications

0 publications found

Variant links:

Genes affected

NFE2L3 (HGNC:7783): (NFE2 like bZIP transcription factor 3) This gene encodes a member of the cap 'n' collar basic-region leucine zipper family of transcription factors. The encoded protein heterodimerizes with small musculoaponeurotic fibrosarcoma factors to bind antioxidant response elements in target genes. This protein is a membrane bound glycoprotein that is targeted to the endoplasmic reticulum and the nuclear envelope. Pseudogenes of this gene are found on chromosomes 16, 17, and 18. [provided by RefSeq, Mar 2009]

NFE2L3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.23921397).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NFE2L3	NM_004289.7 link	c.401C>T	p.Ser134Leu	missense_variant	Exon 1 of 4	ENST00000056233.4	NP_004280.5	Q9Y4A8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NFE2L3	ENST00000056233.4 link	c.401C>T	p.Ser134Leu	missense_variant	Exon 1 of 4	1	NM_004289.7	ENSP00000056233.3		Q9Y4A8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000154

AC:

AN:

1296970

Hom.:

Cov.:

AF XY:

0.00000313

AC XY:

AN XY:

638458

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25740

American (AMR)

AF:

0.00

AC:

AN:

19954

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21722

East Asian (EAS)

AF:

0.00

AC:

AN:

28306

South Asian (SAS)

AF:

0.00

AC:

AN:

67678

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32284

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3824

European-Non Finnish (NFE)

AF:

0.00000192

AC:

AN:

1043708

Other (OTH)

AF:

0.00

AC:

AN:

53754

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.550

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 01, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.401C>T (p.S134L) alteration is located in exon 1 (coding exon 1) of the NFE2L3 gene. This alteration results from a C to T substitution at nucleotide position 401, causing the serine (S) at amino acid position 134 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.49

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.16

Eigen

Benign

0.050

Eigen_PC

Benign

0.092

FATHMM_MKL

Benign

0.62

LIST_S2

Benign

0.57

M_CAP

Pathogenic

0.38

MetaRNN

Benign

0.24

MetaSVM

Benign

-0.99

MutationAssessor

Uncertain

2.2

PhyloP100

0.30

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-2.1

REVEL

Benign

0.076

Sift

Benign

0.042

Sift4G

Uncertain

0.034

Polyphen

0.80

Vest4

0.14

MutPred

0.24

Loss of glycosylation at S134 (P = 0.0022);

MVP

0.46

MPC

1.4

ClinPred

0.86

GERP RS

3.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.11

gMVP

0.25

Mutation Taster

=93/7

polymorphism

(source)

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

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7-26152899-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over