Variant chr12-54292990-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001136023.3(NFE2):c.506G>A(p.Arg169His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000169 in 1,542,358 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

NFE2
NM_001136023.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.07

Variant links:

Genes affected

NFE2 (HGNC:7780): (nuclear factor, erythroid 2) Enables several functions, including WW domain binding activity; identical protein binding activity; and protein N-terminus binding activity. Contributes to cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to act upstream of or within several processes, including labyrinthine layer blood vessel development; negative regulation of bone mineralization; and negative regulation of syncytium formation by plasma membrane fusion. Part of protein-DNA complex. [provided by Alliance of Genome Resources, Apr 2022]

NFE2 links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.1291677).

BS2

High AC in GnomAdExome4 at 22 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NFE2	NM_001136023.3 linkuse as main transcript	c.506G>A	p.Arg169His	missense_variant	3/3	ENST00000435572.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NFE2	ENST00000435572.7 linkuse as main transcript	c.506G>A	p.Arg169His	missense_variant	3/3	1	NM_001136023.3	P1
	ENST00000553061.1 linkuse as main transcript	n.545+15815C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000158

AC:

AN:

1390184

Hom.:

Cov.:

AF XY:

0.0000176

AC XY:

AN XY:

682982

show subpopulations

Gnomad4 AFR exome

AF:

0.0000318

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000186

Gnomad4 OTH exome

AF:

0.0000175

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152174

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 14, 2023

The c.506G>A (p.R169H) alteration is located in exon 3 (coding exon 2) of the NFE2 gene. This alteration results from a G to A substitution at nucleotide position 506, causing the arginine (R) at amino acid position 169 to be replaced by a histidine (H). 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

0.081

BayesDel_addAF

Benign

-0.052

BayesDel_noAF

Benign

-0.31

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.29

T;T;T;T;T

Eigen

Benign

-0.037

Eigen_PC

Benign

-0.059

FATHMM_MKL

Benign

0.22

LIST_S2

Benign

0.82

.;.;.;T;T

M_CAP

Benign

0.0036

MetaRNN

Benign

0.13

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.0

L;L;L;L;.

MutationTaster

Benign

0.99

N;N;N;N

PrimateAI

Benign

0.39

PROVEAN

Benign

0.37

N;N;N;N;N

REVEL

Benign

0.087

Sift

Benign

0.060

T;T;T;T;T

Sift4G

Benign

0.12

T;T;T;T;.

Polyphen

0.92

P;P;P;P;.

Vest4

0.18

MutPred

0.32

Gain of catalytic residue at R167 (P = 0.023);Gain of catalytic residue at R167 (P = 0.023);Gain of catalytic residue at R167 (P = 0.023);Gain of catalytic residue at R167 (P = 0.023);Gain of catalytic residue at R167 (P = 0.023);

MVP

0.40

MPC

1.0

ClinPred

0.74

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.046

gMVP

0.39

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.

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