9-99828486-C-T

Variant names:

• chr9-99828486-C-T
• rs368591388
• NM_006981.4:c.444C>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP7

The NM_006981.4(NR4A3):​c.444C>T​(p.Phe148Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000014 in 1,426,104 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.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NR4A3 NM_006981.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.35
• 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: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP7: Synonymous conserved (PhyloP=1.35 with no splicing effect.

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.444C>T	p.Phe148Phe	synonymous	Exon 3 of 8	NP_008912.2
	NR4A3	NM_173200.3		c.477C>T	p.Phe159Phe	synonymous	Exon 4 of 9	NP_775292.1	Q92570-3
	NR4A3	NM_173199.4		c.444C>T	p.Phe148Phe	synonymous	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.444C>T	p.Phe148Phe	synonymous	Exon 3 of 8	ENSP00000378531.2	Q92570-1
	NR4A3	ENST00000338488.8	TSL:1	c.444C>T	p.Phe148Phe	synonymous	Exon 3 of 5	ENSP00000340301.4	Q92570-2
	NR4A3	ENST00000330847.1	TSL:5	c.477C>T	p.Phe159Phe	synonymous	Exon 2 of 7	ENSP00000333122.1	Q92570-3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000140 AC: 2 AN: 1426104 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 706392

African (AFR) AF: 0.00 AC: 0 AN: 32414

American (AMR) AF: 0.00 AC: 0 AN: 39474

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23502

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39390

South Asian (SAS) AF: 0.00 AC: 0 AN: 80292

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50580

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5584

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1096102

Other (OTH) AF: 0.0000170 AC: 1 AN: 58766

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	14
DANN	Benign	0.84
PhyloP100		1.4

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: rs368591388; hg19: chr9-102590768;