9-99828752-C-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 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. 13/20 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

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]

STX17-DT (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR4A3	NM_006981.4	c.710C>T	p.Ala237Val	missense_variant	Exon 3 of 8	ENST00000395097.7	NP_008912.2
NR4A3	NM_173200.3	c.743C>T	p.Ala248Val	missense_variant	Exon 4 of 9		NP_775292.1
NR4A3	NM_173199.4	c.710C>T	p.Ala237Val	missense_variant	Exon 3 of 5		NP_775291.1
NR4A3	XM_017015162.2	c.710C>T	p.Ala237Val	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.710C>T	p.Ala237Val	missense_variant	Exon 3 of 8	1	NM_006981.4	ENSP00000378531.2

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000190

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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;T;T;.
M_CAP	Pathogenic	0.94	D
MetaRNN	Benign	0.23	T;T;T;T
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	-0.55	N;N;.;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.33	N;N;.;N
REVEL	Benign	0.15
Sift	Benign	0.28	T;T;.;T
Sift4G	Benign	0.55	T;T;T;T
Polyphen		0.015	B;B;B;B
Vest4		0.26
MutPred		0.40		Loss of helix (P = 0.0068);Loss of helix (P = 0.0068);.;.;
MVP		0.69
ClinPred		0.14	T
GERP RS		2.6
Varity_R		0.033
gMVP		0.48

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-102591034;