Genetic Variant NFE2L3:p.Asp44Glu (chr7-26152630-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_004289.7(NFE2L3):c.132C>A(p.Asp44Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000726 in 1,378,260 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.3e-7 ( 0 hom. )

Consequence

NFE2L3
NM_004289.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.524

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: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.053935558).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NFE2L3	NM_004289.7 link	c.132C>A	p.Asp44Glu	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.132C>A	p.Asp44Glu	missense_variant	Exon 1 of 4	1	NM_004289.7	ENSP00000056233.3		Q9Y4A8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.26e-7

AC:

AN:

1378260

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

683248

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

28910

American (AMR)

AF:

0.00

AC:

AN:

35214

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24332

East Asian (EAS)

AF:

0.00

AC:

AN:

32458

South Asian (SAS)

AF:

0.0000128

AC:

AN:

78104

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34926

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5530

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1081354

Other (OTH)

AF:

0.00

AC:

AN:

57432

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

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

Jan 23, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.132C>A (p.D44E) alteration is located in exon 1 (coding exon 1) of the NFE2L3 gene. This alteration results from a C to A substitution at nucleotide position 132, causing the aspartic acid (D) at amino acid position 44 to be replaced by a glutamic acid (E). 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

-0.33

BayesDel_noAF

Benign

-0.72

CADD

Benign

(source)

DANN

Benign

0.73

DEOGEN2

Benign

0.026

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.36

M_CAP

Benign

0.072

MetaRNN

Benign

0.054

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.6

PhyloP100

-0.52

PrimateAI

Uncertain

0.68

PROVEAN

Benign

0.73

REVEL

Benign

0.022

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0060

Vest4

0.12

MutPred

0.33

Gain of catalytic residue at D44 (P = 0.0186);

MVP

0.18

MPC

1.8

ClinPred

0.078

GERP RS

-1.1

PromoterAI

0.063

Neutral

(source)

Varity_R

0.019

gMVP

0.26

Mutation Taster

=96/4

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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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