17-48051304-G-T

Variant names:

• chr17-48051304-G-T
• rs2037243275
• NM_003204.3:c.186G>T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_003204.3(NFE2L1):​c.186G>T​(p.Leu62Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NFE2L1 NM_003204.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.82

Genes affected

NFE2L1 (HGNC:7781): (NFE2 like bZIP transcription factor 1) This gene encodes a protein that is involved in globin gene expression in erythrocytes. Confusion has occurred in bibliographic databases due to the shared symbol of NRF1 for this gene, NFE2L1, and for "nuclear respiratory factor 1" which has an official symbol of NRF1. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NFE2L1	NM_003204.3	c.186G>T	p.Leu62Phe	missense_variant	Exon 2 of 6	ENST00000362042.8	NP_003195.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NFE2L1	ENST00000362042.8	c.186G>T	p.Leu62Phe	missense_variant	Exon 2 of 6	1	NM_003204.3	ENSP00000354855.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461892 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

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: 8.99e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 07, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.186G>T (p.L62F) alteration is located in exon 2 (coding exon 1) of the NFE2L1 gene. This alteration results from a G to T substitution at nucleotide position 186, causing the leucine (L) at amino acid position 62 to be replaced by a phenylalanine (F). 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	0.33
BayesDel_addAF	Uncertain	0.025	T
BayesDel_noAF	Benign	-0.20
CADD	Pathogenic	32
DANN	Benign	0.96
DEOGEN2	Benign	0.33	.;T;.;.;.;.
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.93	D;D;.;D;D;D
M_CAP	Benign	0.016	T
MetaRNN	Uncertain	0.48	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	.;M;M;M;.;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-1.6	.;.;.;N;N;.
REVEL	Benign	0.11
Sift	Benign	0.087	.;.;.;T;D;.
Sift4G	Uncertain	0.041	D;D;D;D;D;D
Polyphen		1.0	.;D;D;D;.;.
Vest4		0.40, 0.54, 0.46, 0.41
MutPred		0.31		Loss of stability (P = 0.0681);Loss of stability (P = 0.0681);Loss of stability (P = 0.0681);Loss of stability (P = 0.0681);Loss of stability (P = 0.0681);Loss of stability (P = 0.0681);
MVP		0.42
MPC		1.2
ClinPred		0.81	D
GERP RS		5.1
Varity_R		0.12
gMVP		0.55

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: rs2037243275; hg19: chr17-46128666;