12-54292400-C-T

Position:

• chr12-54292400-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001136023.3(NFE2):​c.1096G>A​(p.Gly366Arg) 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. 12/20 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)
• Consequence: NFE2 NM_001136023.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.85

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]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3164429).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NFE2	NM_001136023.3	c.1096G>A	p.Gly366Arg	missense_variant	3/3	ENST00000435572.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NFE2	ENST00000435572.7	c.1096G>A	p.Gly366Arg	missense_variant	3/3	1	NM_001136023.3	P1
	ENST00000553061.1	n.545+15225C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 18, 2022

The c.1096G>A (p.G366R) 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 1096, causing the glycine (G) at amino acid position 366 to be replaced by an arginine (R). 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	0.19
BayesDel_addAF	Benign	-0.041	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T;T;T;T
Eigen	Benign	-0.020
Eigen_PC	Benign	0.082
FATHMM_MKL	Benign	0.41	N
LIST_S2	Benign	0.78	.;.;.;T
M_CAP	Benign	0.0020	T
MetaRNN	Benign	0.32	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.13	N;N;N;N
MutationTaster	Benign	0.65	N;N;N;N
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.96	N;N;N;N
REVEL	Benign	0.086
Sift	Benign	0.081	T;T;T;T
Sift4G	Benign	0.15	T;T;T;T
Polyphen		0.62	P;P;P;P
Vest4		0.43
MutPred		0.28		Gain of catalytic residue at F361 (P = 0.0207);Gain of catalytic residue at F361 (P = 0.0207);Gain of catalytic residue at F361 (P = 0.0207);Gain of catalytic residue at F361 (P = 0.0207);
MVP		0.20
MPC		0.98
ClinPred		0.77	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.084
gMVP		0.11

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

Other links and lift over

dbSNP: rs1944324674; hg19: chr12-54686184; COSMIC: COSV100380848; COSMIC: COSV100380848;