rs141363120

chr2-177231678-G-Achr2-177231678-G-C

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_006164.5(NFE2L2):c.925C>T(p.Leu309Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00337 in 1,614,194 control chromosomes in the GnomAD database, including 14 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L309V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0026 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0035 (11 hom.)
• Consequence: NFE2L2 NM_006164.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2 O:1
• Conservation: PhyloP100: 1.43

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0072987676).
• BP6: Variant 2-177231678-G-A is Benign according to our data. Variant chr2-177231678-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 134904.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 389 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NFE2L2	NM_006164.5	c.925C>T	p.Leu309Phe	missense_variant	5/5	ENST00000397062.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NFE2L2	ENST00000397062.8	c.925C>T	p.Leu309Phe	missense_variant	5/5	1	NM_006164.5	A1

Frequencies

GnomAD3 genomes AF: 0.00256 AC: 389 AN: 152202 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.000796

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00183

Gnomad ASJ AF: 0.0288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00316

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00301 AC: 751 AN: 249802 Hom.: 3 AF XY: 0.00289 AC XY: 391 AN XY: 135512

Gnomad AFR exome AF: 0.00135

Gnomad AMR exome AF: 0.00298

Gnomad ASJ exome AF: 0.0238

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.0000927

Gnomad NFE exome AF: 0.00305

Gnomad OTH exome AF: 0.00577

GnomAD4 exome AF: 0.00346 AC: 5051 AN: 1461874 Hom.: 11 Cov.: 31 AF XY: 0.00331 AC XY: 2406 AN XY: 727240

Gnomad4 AFR exome AF: 0.00111

Gnomad4 AMR exome AF: 0.00297

Gnomad4 ASJ exome AF: 0.0233

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000255

Gnomad4 FIN exome AF: 0.000243

Gnomad4 NFE exome AF: 0.00351

Gnomad4 OTH exome AF: 0.00503

GnomAD4 genome AF: 0.00255 AC: 389 AN: 152320 Hom.: 3 Cov.: 33 AF XY: 0.00227 AC XY: 169 AN XY: 74480

Gnomad4 AFR AF: 0.000818

Gnomad4 AMR AF: 0.00183

Gnomad4 ASJ AF: 0.0288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00316

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00403 Hom.: 4

Bravo AF: 0.00299

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.00190 AC: 8

ESP6500EA AF: 0.00423 AC: 36

ExAC AF: 0.00253 AC: 307

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00409

EpiControl AF: 0.00391

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	NFE2L2: BP4, BS1, BS2 -

not specified Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.16
Cadd	Benign	18
Dann	Uncertain	0.99
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.0073	T;T;T;T
MetaSVM	Benign	-0.80	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.8	N;N;N;.
REVEL	Uncertain	0.30
Sift	Uncertain	0.016	D;D;D;.
Sift4G	Benign	0.10	T;T;T;T
Polyphen		1.0	.;D;.;.
Vest4		0.080
MVP		0.38
MPC		0.17
ClinPred		0.040	T
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.18
gMVP		0.33

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: rs141363120; hg19: chr2-178096406; COSMIC: COSV67961447; COSMIC: COSV67961447;