rs35577826

Variant names:

• chr2-177232457-A-C
• rs35577826
• NM_006164.5:c.529T>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_006164.5(NFE2L2):​c.529T>G​(p.Leu177Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000334 in 1,614,130 control chromosomes in the GnomAD database, including 2 homozygotes. 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 Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L177S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0018 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00018 (1 hom.)
• Consequence: NFE2L2 NM_006164.5 missense
• Clinical Significance: Benign criteria provided, single submitter B:2 O:1
• Conservation: PhyloP100: -0.129
• Publications: 9 publications found

Genes affected

NFE2L2 (HGNC:7782): (NFE2 like bZIP transcription factor 2) This gene encodes a transcription factor which is a member of a small family of basic leucine zipper (bZIP) proteins. The encoded transcription factor regulates genes which contain antioxidant response elements (ARE) in their promoters; many of these genes encode proteins involved in response to injury and inflammation which includes the production of free radicals. Multiple transcript variants encoding different isoforms have been characterized for this gene. [provided by RefSeq, Sep 2015]

NFE2L2 Gene-Disease associations (from GenCC):

• immunodeficiency, developmental delay, and hypohomocysteinemia

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Illumina, ClinGen, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003155291).
• BP6: Variant 2-177232457-A-C is Benign according to our data. Variant chr2-177232457-A-C is described in ClinVar as Benign. ClinVar VariationId is 134901.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 273 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006164.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NFE2L2	NM_006164.5	MANE Select	c.529T>G	p.Leu177Val	missense	Exon 4 of 5	NP_006155.2
	NFE2L2	NM_001145412.3		c.481T>G	p.Leu161Val	missense	Exon 4 of 5	NP_001138884.1	Q16236-2
	NFE2L2	NM_001313900.1		c.481T>G	p.Leu161Val	missense	Exon 4 of 5	NP_001300829.1	Q16236-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NFE2L2	ENST00000397062.8	TSL:1 MANE Select	c.529T>G	p.Leu177Val	missense	Exon 4 of 5	ENSP00000380252.3	Q16236-1
	NFE2L2	ENST00000397063.9	TSL:1	c.481T>G	p.Leu161Val	missense	Exon 4 of 5	ENSP00000380253.4	Q16236-2
	NFE2L2	ENST00000421929.6	TSL:1	c.481T>G	p.Leu161Val	missense	Exon 4 of 5	ENSP00000412191.2	Q16236-2

Frequencies

GnomAD3 genomes AF: 0.00179 AC: 273 AN: 152200 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00634

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000462 AC: 115 AN: 248914 AF XY: 0.000318

Gnomad AFR exome AF: 0.00713

Gnomad AMR exome AF: 0.0000870

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.000182 AC: 266 AN: 1461812 Hom.: 1 Cov.: 30 AF XY: 0.000157 AC XY: 114 AN XY: 727206

African (AFR) AF: 0.00714 AC: 239 AN: 33480

American (AMR) AF: 0.000179 AC: 8 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111960

Other (OTH) AF: 0.000281 AC: 17 AN: 60394

GnomAD4 genome AF: 0.00179 AC: 273 AN: 152318 Hom.: 1 Cov.: 33 AF XY: 0.00161 AC XY: 120 AN XY: 74490

African (AFR) AF: 0.00633 AC: 263 AN: 41576

American (AMR) AF: 0.000523 AC: 8 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.000756 Hom.: 1

Bravo AF: 0.00214

ESP6500AA AF: 0.00606 AC: 23

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000488 AC: 59

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	0.18
DANN	Benign	0.66
DEOGEN2	Benign	0.055	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.092	N
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.0064	T
MetaRNN	Benign	0.0032	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
PhyloP100		-0.13
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.023
Sift	Benign	0.20	T
Sift4G	Benign	0.51	T
Polyphen		0.018	B
Vest4		0.075
MVP		0.32
MPC		0.15
ClinPred		0.0090	T
GERP RS		1.1
PromoterAI		0.018	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.022
gMVP		0.098
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs35577826; hg19: chr2-178097185;