9-99828656-C-T

Variant names:

• chr9-99828656-C-T
• rs1466169303
• NM_006981.4:c.614C>T

Variant summary

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

The NM_006981.4(NR4A3):​c.614C>T​(p.Pro205Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000132 in 151,548 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. P205R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NR4A3 NM_006981.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.36
• 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=0.29515842).

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.614C>T	p.Pro205Leu	missense	Exon 3 of 8	NP_008912.2
	NR4A3	NM_173200.3		c.647C>T	p.Pro216Leu	missense	Exon 4 of 9	NP_775292.1	Q92570-3
	NR4A3	NM_173199.4		c.614C>T	p.Pro205Leu	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.614C>T	p.Pro205Leu	missense	Exon 3 of 8	ENSP00000378531.2	Q92570-1
	NR4A3	ENST00000338488.8	TSL:1	c.614C>T	p.Pro205Leu	missense	Exon 3 of 5	ENSP00000340301.4	Q92570-2
	NR4A3	ENST00000330847.1	TSL:5	c.647C>T	p.Pro216Leu	missense	Exon 2 of 7	ENSP00000333122.1	Q92570-3

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151548 Hom.: 0 Cov.: 31

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: 0.0000295

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1270834 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 623984

African (AFR) AF: 0.00 AC: 0 AN: 25124

American (AMR) AF: 0.00 AC: 0 AN: 17854

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20588

East Asian (EAS) AF: 0.00 AC: 0 AN: 27580

South Asian (SAS) AF: 0.00 AC: 0 AN: 63980

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 31518

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3952

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1027762

Other (OTH) AF: 0.00 AC: 0 AN: 52476

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151548 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74004

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41366

American (AMR) AF: 0.00 AC: 0 AN: 15186

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000295 AC: 2 AN: 67830

Other (OTH) AF: 0.00 AC: 0 AN: 2080

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0296732), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Uncertain	0.017	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.065
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.81	T
M_CAP	Pathogenic	0.96	D
MetaRNN	Benign	0.30	T
MetaSVM	Benign	-0.41	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.4
PrimateAI	Pathogenic	0.92	D
PROVEAN	Benign	-0.69	N
REVEL	Uncertain	0.31
Sift	Benign	0.12	T
Sift4G	Benign	0.38	T
Polyphen		0.88	P
Vest4		0.29
MutPred		0.28		Gain of loop (P = 0.0502)
MVP		0.78
ClinPred		0.19	T
GERP RS		4.0
Varity_R		0.083
gMVP		0.33
Mutation Taster		=75/25	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: rs1466169303; hg19: chr9-102590938;