rs575180948

Variant names:

• chr9-99828708-C-A
• rs575180948
• NM_006981.4:c.666C>A

Your query was ambiguous. Multiple possible variants found:

• chr9-99828708-C-A
• chr9-99828708-C-G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_006981.4(NR4A3):​c.666C>A​(p.Ser222Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000016 in 1,312,150 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000086 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: NR4A3 NM_006981.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.08
• Publications: 1 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.22634095).
• BS2: High AC in GnomAd4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR4A3	NM_006981.4	c.666C>A	p.Ser222Arg	missense_variant	Exon 3 of 8	ENST00000395097.7	NP_008912.2
NR4A3	NM_173200.3	c.699C>A	p.Ser233Arg	missense_variant	Exon 4 of 9		NP_775292.1
NR4A3	NM_173199.4	c.666C>A	p.Ser222Arg	missense_variant	Exon 3 of 5		NP_775291.1
NR4A3	XM_017015162.2	c.666C>A	p.Ser222Arg	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.666C>A	p.Ser222Arg	missense_variant	Exon 3 of 8	1	NM_006981.4	ENSP00000378531.2

Frequencies

GnomAD3 genomes AF: 0.0000858 AC: 13 AN: 151576 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000657

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000689 AC: 8 AN: 1160462 Hom.: 0 Cov.: 31 AF XY: 0.00000712 AC XY: 4 AN XY: 561896

African (AFR) AF: 0.000345 AC: 8 AN: 23196

American (AMR) AF: 0.00 AC: 0 AN: 8824

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15304

East Asian (EAS) AF: 0.00 AC: 0 AN: 26714

South Asian (SAS) AF: 0.00 AC: 0 AN: 41778

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 26026

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3246

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 968536

Other (OTH) AF: 0.00 AC: 0 AN: 46838

GnomAD4 genome AF: 0.0000857 AC: 13 AN: 151688 Hom.: 0 Cov.: 31 AF XY: 0.0000809 AC XY: 6 AN XY: 74144

African (AFR) AF: 0.000289 AC: 12 AN: 41468

American (AMR) AF: 0.0000656 AC: 1 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5146

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10394

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67838

Other (OTH) AF: 0.00 AC: 0 AN: 2102

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000136

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Uncertain	0.064	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	18
DANN	Benign	0.93
DEOGEN2	Benign	0.23	.;T;.;.
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.32
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.75	T;T;T;.
M_CAP	Pathogenic	0.90	D
MetaRNN	Benign	0.23	T;T;T;T
MetaSVM	Benign	-0.49	T
MutationAssessor	Benign	1.4	L;L;.;.
PhyloP100		1.1
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-0.46	N;N;.;N
REVEL	Uncertain	0.47
Sift	Benign	0.49	T;T;.;T
Sift4G	Benign	0.60	T;T;T;T
Polyphen		0.85	P;B;B;B
Vest4		0.15
MutPred		0.38		Loss of glycosylation at S222 (P = 0.0019);Loss of glycosylation at S222 (P = 0.0019);.;.;
MVP		0.68
ClinPred		0.10	T
GERP RS		0.79
Varity_R		0.079
gMVP		0.48
Mutation Taster		=91/9	polymorphism

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

dbSNP: rs575180948; hg19: chr9-102590990;