NM_006981.4:c.710C>T

Variant names:

• chr9-99828752-C-T
• rs1198610030
• NM_006981.4:c.710C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006981.4(NR4A3):​c.710C>T​(p.Ala237Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000833 in 1,199,982 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A237E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 8.3e-7 (0 hom.)
• Consequence: NR4A3 NM_006981.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.09
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22879663).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006981.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR4A3	NM_006981.4	MANE Select	c.710C>T	p.Ala237Val	missense	Exon 3 of 8	NP_008912.2
	NR4A3	NM_173200.3		c.743C>T	p.Ala248Val	missense	Exon 4 of 9	NP_775292.1	Q92570-3
	NR4A3	NM_173199.4		c.710C>T	p.Ala237Val	missense	Exon 3 of 5	NP_775291.1	Q92570-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR4A3	ENST00000395097.7	TSL:1 MANE Select	c.710C>T	p.Ala237Val	missense	Exon 3 of 8	ENSP00000378531.2	Q92570-1
	NR4A3	ENST00000338488.8	TSL:1	c.710C>T	p.Ala237Val	missense	Exon 3 of 5	ENSP00000340301.4	Q92570-2
	NR4A3	ENST00000330847.1	TSL:5	c.743C>T	p.Ala248Val	missense	Exon 2 of 7	ENSP00000333122.1	Q92570-3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 8.33e-7 AC: 1 AN: 1199982 Hom.: 0 Cov.: 31 AF XY: 0.00000171 AC XY: 1 AN XY: 585846

African (AFR) AF: 0.00 AC: 0 AN: 24172

American (AMR) AF: 0.00 AC: 0 AN: 12102

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17584

East Asian (EAS) AF: 0.00 AC: 0 AN: 27318

South Asian (SAS) AF: 0.0000190 AC: 1 AN: 52620

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28026

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3446

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 986132

Other (OTH) AF: 0.00 AC: 0 AN: 48582

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.023	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	T
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.72
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.61	T
M_CAP	Pathogenic	0.94	D
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	-0.55	N
PhyloP100		2.1
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.33	N
REVEL	Benign	0.15
Sift	Benign	0.28	T
Sift4G	Benign	0.55	T
Polyphen		0.015	B
Vest4		0.26
MutPred		0.40		Loss of helix (P = 0.0068)
MVP		0.69
ClinPred		0.14	T
GERP RS		2.6
Varity_R		0.033
gMVP		0.48
Mutation Taster		=86/14	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: rs1198610030; hg19: chr9-102591034;