9-99828856-G-C

Variant names:

• chr9-99828856-G-C
• NM_006981.4:c.814G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_006981.4(NR4A3):​c.814G>C​(p.Gly272Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: NR4A3 NM_006981.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.38
• Publications: 0 publications found

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]

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3647893).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR4A3	NM_006981.4	c.814G>C	p.Gly272Arg	missense_variant	Exon 3 of 8	ENST00000395097.7	NP_008912.2
NR4A3	NM_173200.3	c.847G>C	p.Gly283Arg	missense_variant	Exon 4 of 9		NP_775292.1
NR4A3	NM_173199.4	c.814G>C	p.Gly272Arg	missense_variant	Exon 3 of 5		NP_775291.1
NR4A3	XM_017015162.2	c.814G>C	p.Gly272Arg	missense_variant	Exon 4 of 9		XP_016870651.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NR4A3	ENST00000395097.7	c.814G>C	p.Gly272Arg	missense_variant	Exon 3 of 8	1	NM_006981.4	ENSP00000378531.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 27, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.847G>C (p.G283R) alteration is located in exon 4 (coding exon 2) of the NR4A3 gene. This alteration results from a G to C substitution at nucleotide position 847, causing the glycine (G) at amino acid position 283 to be replaced by an arginine (R). 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	0.48
BayesDel_addAF	Uncertain	0.091	D
BayesDel_noAF	Benign	-0.11
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	.;T;.;.
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.74	T;T;T;.
M_CAP	Pathogenic	0.33	D
MetaRNN	Benign	0.36	T;T;T;T
MetaSVM	Uncertain	0.47	D
MutationAssessor	Benign	0.69	N;N;.;.
PhyloP100		5.4
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.3	N;N;.;N
REVEL	Uncertain	0.37
Sift	Benign	0.41	T;T;.;T
Sift4G	Benign	0.14	T;T;T;T
Polyphen		0.96	D;P;P;P
Vest4		0.47
MutPred		0.16		Loss of glycosylation at S269 (P = 0.0672);Loss of glycosylation at S269 (P = 0.0672);.;.;
MVP		0.92
ClinPred		0.79	D
GERP RS		4.9
Varity_R		0.25
gMVP		0.35
Mutation Taster		=47/53	disease causing

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

Other links and lift over

hg19: chr9-102591138;