7-129727323-G-A

Position:

• chr7-129727323-G-A

Variant summary

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

The NM_005011.5(NRF1):​c.1306G>A​(p.Ala436Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,456,772 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NRF1 NM_005011.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.27

Genes affected

NRF1 (HGNC:7996): (nuclear respiratory factor 1) This gene encodes a protein that homodimerizes and functions as a transcription factor which activates the expression of some key metabolic genes regulating cellular growth and nuclear genes required for respiration, heme biosynthesis, and mitochondrial DNA transcription and replication. The protein has also been associated with the regulation of neurite outgrowth. Alternative splicing results in multiple transcript variants. Confusion has occurred in bibliographic databases due to the shared symbol of NRF1 for this gene and for "nuclear factor (erythroid-derived 2)-like 1" which has an official symbol of NFE2L1. [provided by RefSeq, May 2014]

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=0.34799314).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NRF1	NM_005011.5	c.1306G>A	p.Ala436Thr	missense_variant	10/11	ENST00000393232.6
NRF1	NM_001293163.2	c.1306G>A	p.Ala436Thr	missense_variant	10/12
NRF1	NM_001040110.2	c.1306G>A	p.Ala436Thr	missense_variant	10/11
NRF1	NM_001293164.2	c.823G>A	p.Ala275Thr	missense_variant	9/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NRF1	ENST00000393232.6	c.1306G>A	p.Ala436Thr	missense_variant	10/11	1	NM_005011.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1456772 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 724760

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

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

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 06, 2022

The c.1306G>A (p.A436T) alteration is located in exon 10 (coding exon 9) of the NRF1 gene. This alteration results from a G to A substitution at nucleotide position 1306, causing the alanine (A) at amino acid position 436 to be replaced by a threonine (T). 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	0.52
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.17	T;T;.;T;.
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D;.;.;.;D
M_CAP	Benign	0.0044	T
MetaRNN	Benign	0.35	T;T;T;T;T
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	1.2	L;L;L;L;L
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-1.9	N;N;N;N;.
REVEL	Benign	0.28
Sift	Uncertain	0.0070	D;D;T;D;.
Sift4G	Benign	0.14	T;T;T;T;T
Polyphen		1.0	D;D;.;D;.
Vest4		0.75
MutPred		0.38		Gain of catalytic residue at A436 (P = 0.0281);Gain of catalytic residue at A436 (P = 0.0281);Gain of catalytic residue at A436 (P = 0.0281);Gain of catalytic residue at A436 (P = 0.0281);Gain of catalytic residue at A436 (P = 0.0281);
MVP		0.21
MPC		1.5
ClinPred		0.88	D
GERP RS		6.0
Varity_R		0.22
gMVP		0.88

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: rs1803472021; hg19: chr7-129367163; COSMIC: COSV56211922;