rs3735006

Positions:

• chr7-129690513-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Moderate BP7 BA1

The NM_005011.5(NRF1):​c.573C>T​(p.Asp191=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0537 in 1,614,046 control chromosomes in the GnomAD database, including 2,590 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.044 (174 hom., cov: 32)
  • Exomes 𝑓: 0.055 (2416 hom.)
• Consequence: NRF1 NM_005011.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.14

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 Benign. Variant got -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP7: Synonymous conserved (PhyloP=-2.14 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0596 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NRF1	NM_005011.5	c.573C>T	p.Asp191=	synonymous_variant	5/11	ENST00000393232.6	NP_005002.3
NRF1	NM_001293163.2	c.573C>T	p.Asp191=	synonymous_variant	5/12		NP_001280092.1
NRF1	NM_001040110.2	c.573C>T	p.Asp191=	synonymous_variant	5/11		NP_001035199.1
NRF1	NM_001293164.2	c.90C>T	p.Asp30=	synonymous_variant	4/10		NP_001280093.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NRF1	ENST00000393232.6	c.573C>T	p.Asp191=	synonymous_variant	5/11	1	NM_005011.5	ENSP00000376924	P1

Frequencies

GnomAD3 genomes AF: 0.0441 AC: 6712 AN: 152124 Hom.: 174 Cov.: 32

Gnomad AFR AF: 0.0162

Gnomad AMI AF: 0.0560

Gnomad AMR AF: 0.0496

Gnomad ASJ AF: 0.0279

Gnomad EAS AF: 0.0613

Gnomad SAS AF: 0.0216

Gnomad FIN AF: 0.0380

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.0611

Gnomad OTH AF: 0.0536

GnomAD3 exomes AF: 0.0458 AC: 11500 AN: 251230 Hom.: 328 AF XY: 0.0460 AC XY: 6247 AN XY: 135764

Gnomad AFR exome AF: 0.0150

Gnomad AMR exome AF: 0.0339

Gnomad ASJ exome AF: 0.0304

Gnomad EAS exome AF: 0.0589

Gnomad SAS exome AF: 0.0216

Gnomad FIN exome AF: 0.0355

Gnomad NFE exome AF: 0.0610

Gnomad OTH exome AF: 0.0545

GnomAD4 exome AF: 0.0547 AC: 79910 AN: 1461804 Hom.: 2416 Cov.: 31 AF XY: 0.0539 AC XY: 39171 AN XY: 727202

Gnomad4 AFR exome AF: 0.0142

Gnomad4 AMR exome AF: 0.0349

Gnomad4 ASJ exome AF: 0.0323

Gnomad4 EAS exome AF: 0.0612

Gnomad4 SAS exome AF: 0.0213

Gnomad4 FIN exome AF: 0.0320

Gnomad4 NFE exome AF: 0.0607

Gnomad4 OTH exome AF: 0.0507

GnomAD4 genome AF: 0.0440 AC: 6706 AN: 152242 Hom.: 174 Cov.: 32 AF XY: 0.0436 AC XY: 3249 AN XY: 74448

Gnomad4 AFR AF: 0.0162

Gnomad4 AMR AF: 0.0495

Gnomad4 ASJ AF: 0.0279

Gnomad4 EAS AF: 0.0614

Gnomad4 SAS AF: 0.0210

Gnomad4 FIN AF: 0.0380

Gnomad4 NFE AF: 0.0612

Gnomad4 OTH AF: 0.0531

Alfa AF: 0.0525 Hom.: 162

Bravo AF: 0.0440

Asia WGS AF: 0.0310 AC: 109 AN: 3478

EpiCase AF: 0.0624

EpiControl AF: 0.0690

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	2.3
DANN	Benign	0.71

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: rs3735006; hg19: chr7-129330353;