rs765286795

Variant names:

• chr7-26152844-G-A
• rs765286795
• NM_004289.7:c.346G>A

Your query was ambiguous. Multiple possible variants found:

• chr7-26152844-G-A
• chr7-26152844-G-C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_004289.7(NFE2L3):​c.346G>A​(p.Val116Met) variant causes a missense change. The variant allele was found at a frequency of 0.000634 in 1,474,794 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V116L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00045 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00066 (1 hom.)
• Consequence: NFE2L3 NM_004289.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.08
• Publications: 2 publications found

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]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.18875772).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NFE2L3	NM_004289.7	c.346G>A	p.Val116Met	missense_variant	Exon 1 of 4	ENST00000056233.4	NP_004280.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NFE2L3	ENST00000056233.4	c.346G>A	p.Val116Met	missense_variant	Exon 1 of 4	1	NM_004289.7	ENSP00000056233.3

Frequencies

GnomAD3 genomes AF: 0.000447 AC: 68 AN: 152088 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000982

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: 0.000677

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000621 AC: 48 AN: 77328 AF XY: 0.000539

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00148

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000844

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000656 AC: 867 AN: 1322598 Hom.: 1 Cov.: 31 AF XY: 0.000641 AC XY: 418 AN XY: 652188

African (AFR) AF: 0.000224 AC: 6 AN: 26736

American (AMR) AF: 0.00175 AC: 46 AN: 26350

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23408

East Asian (EAS) AF: 0.00 AC: 0 AN: 28676

South Asian (SAS) AF: 0.0000822 AC: 6 AN: 72998

European-Finnish (FIN) AF: 0.0000912 AC: 3 AN: 32900

Middle Eastern (MID) AF: 0.000255 AC: 1 AN: 3916

European-Non Finnish (NFE) AF: 0.000731 AC: 770 AN: 1052710

Other (OTH) AF: 0.000637 AC: 35 AN: 54904

GnomAD4 genome AF: 0.000447 AC: 68 AN: 152196 Hom.: 0 Cov.: 32 AF XY: 0.000484 AC XY: 36 AN XY: 74432

African (AFR) AF: 0.000120 AC: 5 AN: 41564

American (AMR) AF: 0.000981 AC: 15 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10584

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.000677 AC: 46 AN: 67972

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000847 Hom.: 0

Bravo AF: 0.000461

ExAC AF: 0.0000421 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 26, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.346G>A (p.V116M) alteration is located in exon 1 (coding exon 1) of the NFE2L3 gene. This alteration results from a G to A substitution at nucleotide position 346, causing the valine (V) at amino acid position 116 to be replaced by a methionine (M). 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	Uncertain	0.34
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.33
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.10	T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.79	T
M_CAP	Uncertain	0.25	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		5.1
PrimateAI	Pathogenic	0.94	D
PROVEAN	Benign	-0.85	N
REVEL	Benign	0.13
Sift	Uncertain	0.025	D
Sift4G	Uncertain	0.060	T
Polyphen		1.0	D
Vest4		0.41
MutPred		0.27		Loss of sheet (P = 0.0315);
MVP		0.59
MPC		2.0
ClinPred		0.10	T
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.16
gMVP		0.47
Mutation Taster		=84/16	polymorphism

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: rs765286795; hg19: chr7-26192464;