Genetic Variant NR4A3:p.Ala237Val (chr9-99828752-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.09

Publications

0 publications found

Variant links:

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]

NR4A3 links:

NAMA (HGNC:42408): (non-protein coding RNA, associated with MAP kinase pathway and growth arrest)

NAMA links:

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ACMG classification

Classification was made for transcript

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).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR4A3	NM_006981.4 link	c.710C>T	p.Ala237Val	missense_variant	Exon 3 of 8	ENST00000395097.7	NP_008912.2	Q92570-1A0A024R168
NR4A3	NM_173200.3 link	c.743C>T	p.Ala248Val	missense_variant	Exon 4 of 9		NP_775292.1	Q92570-3
NR4A3	NM_173199.4 link	c.710C>T	p.Ala237Val	missense_variant	Exon 3 of 5		NP_775291.1	Q92570-2
NR4A3	XM_017015162.2 link	c.710C>T	p.Ala237Val	missense_variant	Exon 4 of 9		XP_016870651.1	Q92570-1A0A024R168

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NR4A3	ENST00000395097.7 link	c.710C>T	p.Ala237Val	missense_variant	Exon 3 of 8	1	NM_006981.4	ENSP00000378531.2		Q92570-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

8.33e-7

AC:

AN:

1199982

Hom.:

Cov.:

AF XY:

0.00000171

AC XY:

AN XY:

585846

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

24172

American (AMR)

AF:

0.00

AC:

AN:

12102

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17584

East Asian (EAS)

AF:

0.00

AC:

AN:

27318

South Asian (SAS)

AF:

0.0000190

AC:

AN:

52620

European-Finnish (FIN)

AF:

0.00

AC:

AN:

28026

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3446

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

986132

Other (OTH)

AF:

0.00

AC:

AN:

48582

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

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

BayesDel_noAF

Benign

-0.27

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.19

.;T;.;.

Eigen

Benign

-0.82

Eigen_PC

Benign

-0.72

FATHMM_MKL

Benign

0.43

LIST_S2

Benign

0.61

T;T;T;.

M_CAP

Pathogenic

0.94

MetaRNN

Benign

0.23

T;T;T;T

MetaSVM

Benign

-0.62

MutationAssessor

Benign

-0.55

N;N;.;.

PhyloP100

2.1

PrimateAI

Pathogenic

0.81

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

GERP RS

2.6

Varity_R

0.033

gMVP

0.48

Mutation Taster

=86/14

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over