NM_006981.4:c.579C>G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4BS2

The NM_006981.4(NR4A3):c.579C>G(p.Phe193Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000939 in 1,491,298 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: 𝑓 0.000026 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

NR4A3
NM_006981.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.01

Publications

0 publications found

Variant links:

Genes affected

NR4A3 (HGNC:7982): (nuclear receptor subfamily 4 group A member 3) This gene encodes a member of the steroid-thyroid hormone-retinoid receptor superfamily. The encoded protein may act as a transcriptional activator. The protein can efficiently bind the NGFI-B Response Element (NBRE). Three different versions of extraskeletal myxoid chondrosarcomas (EMCs) are the result of reciprocal translocations between this gene and other genes. The translocation breakpoints are associated with Nuclear Receptor Subfamily 4, Group A, Member 3 (on chromosome 9) and either Ewing Sarcome Breakpoint Region 1 (on chromosome 22), RNA Polymerase II, TATA Box-Binding Protein-Associated Factor, 68-KD (on chromosome 17), or Transcription factor 12 (on chromosome 15). Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Mar 2010]

NR4A3 links:

NAMA (HGNC:42408): (non-protein coding RNA, associated with MAP kinase pathway and growth arrest)

NAMA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.29104966).

BS2

High AC in GnomAdExome4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR4A3	NM_006981.4 link	c.579C>G	p.Phe193Leu	missense_variant	Exon 3 of 8	ENST00000395097.7	NP_008912.2	Q92570-1A0A024R168
NR4A3	NM_173200.3 link	c.612C>G	p.Phe204Leu	missense_variant	Exon 4 of 9		NP_775292.1	Q92570-3
NR4A3	NM_173199.4 link	c.579C>G	p.Phe193Leu	missense_variant	Exon 3 of 5		NP_775291.1	Q92570-2
NR4A3	XM_017015162.2 link	c.579C>G	p.Phe193Leu	missense_variant	Exon 4 of 9		XP_016870651.1	Q92570-1A0A024R168

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NR4A3	ENST00000395097.7 link	c.579C>G	p.Phe193Leu	missense_variant	Exon 3 of 8	1	NM_006981.4	ENSP00000378531.2		Q92570-1

Frequencies

GnomAD3 genomes

AF:

0.0000264

AC:

AN:

151788

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000589

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000228

AC:

AN:

87616

AF XY:

0.0000393

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000572

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000747

AC:

AN:

1339510

Hom.:

Cov.:

AF XY:

0.00000605

AC XY:

AN XY:

661510

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26968

American (AMR)

AF:

0.00

AC:

AN:

27900

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23112

East Asian (EAS)

AF:

0.00

AC:

AN:

29814

South Asian (SAS)

AF:

0.00

AC:

AN:

74240

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34060

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4670

European-Non Finnish (NFE)

AF:

0.00000941

AC:

AN:

1063136

Other (OTH)

AF:

0.00

AC:

AN:

55610

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.420

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000264

AC:

AN:

151788

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74132

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41396

American (AMR)

AF:

0.00

AC:

AN:

15216

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10514

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000589

AC:

AN:

67870

Other (OTH)

AF:

0.00

AC:

AN:

2084

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 08, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.612C>G (p.F204L) alteration is located in exon 4 (coding exon 2) of the NR4A3 gene. This alteration results from a C to G substitution at nucleotide position 612, causing the phenylalanine (F) at amino acid position 204 to be replaced by a leucine (L). 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

0.54

BayesDel_addAF

Uncertain

0.084

BayesDel_noAF

Benign

-0.12

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.52

.;D;.;.

Eigen

Benign

-0.17

Eigen_PC

Benign

-0.075

FATHMM_MKL

Uncertain

0.81

LIST_S2

Uncertain

0.91

D;D;D;.

M_CAP

Pathogenic

0.87

MetaRNN

Benign

0.29

T;T;T;T

MetaSVM

Benign

-0.34

MutationAssessor

Benign

0.81

L;L;.;.

PhyloP100

3.0

PrimateAI

Pathogenic

0.94

PROVEAN

Benign

-2.1

N;N;.;N

REVEL

Uncertain

0.41

Sift

Benign

0.092

T;T;.;T

Sift4G

Benign

0.14

T;T;T;T

Polyphen

0.33

B;B;B;B

Vest4

0.36

MutPred

0.20

Loss of helix (P = 0.0237);Loss of helix (P = 0.0237);.;.;

MVP

0.91

ClinPred

0.12

GERP RS

2.9

Varity_R

0.16

gMVP

0.52

Mutation Taster

=82/18

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

NM_006981.4:c.579C>G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over