9-99828440-T-C

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_006981.4(NR4A3):c.398T>C(p.Met133Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000177 in 1,582,296 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

NR4A3
NM_006981.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.02

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAd4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR4A3	NM_006981.4 link	c.398T>C	p.Met133Thr	missense_variant	Exon 3 of 8	ENST00000395097.7	NP_008912.2	Q92570-1A0A024R168
NR4A3	NM_173200.3 link	c.431T>C	p.Met144Thr	missense_variant	Exon 4 of 9		NP_775292.1	Q92570-3
NR4A3	NM_173199.4 link	c.398T>C	p.Met133Thr	missense_variant	Exon 3 of 5		NP_775291.1	Q92570-2
NR4A3	XM_017015162.2 link	c.398T>C	p.Met133Thr	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.398T>C	p.Met133Thr	missense_variant	Exon 3 of 8	1	NM_006981.4	ENSP00000378531.2		Q92570-1

Frequencies

GnomAD3 genomes

AF:

0.0000529

AC:

AN:

151322

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000243

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000197

Gnomad ASJ

AF:

0.000289

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000443

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000232

AC:

AN:

215496

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000313

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000316

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000140

AC:

AN:

1430858

Hom.:

Cov.:

AF XY:

0.0000141

AC XY:

AN XY:

708352

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33058

American (AMR)

AF:

0.0000473

AC:

AN:

42272

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23436

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39542

South Asian (SAS)

AF:

0.0000125

AC:

AN:

79898

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51340

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5594

European-Non Finnish (NFE)

AF:

0.0000128

AC:

AN:

1096590

Other (OTH)

AF:

0.0000338

AC:

AN:

59128

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000528

AC:

AN:

151438

Hom.:

Cov.:

AF XY:

0.0000540

AC XY:

AN XY:

74040

show subpopulations

African (AFR)

AF:

0.0000242

AC:

AN:

41306

American (AMR)

AF:

0.000197

AC:

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.000289

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5080

South Asian (SAS)

AF:

0.00

AC:

AN:

4768

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10508

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000443

AC:

AN:

67746

Other (OTH)

AF:

0.00

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000612

Hom.:

Bravo

AF:

0.000102

ExAC

AF:

0.0000249

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 09, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.431T>C (p.M144T) alteration is located in exon 4 (coding exon 2) of the NR4A3 gene. This alteration results from a T to C substitution at nucleotide position 431, causing the methionine (M) at amino acid position 144 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.57

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.26

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.41

.;T;.;.

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.49

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.92

D;D;D;.

M_CAP

Uncertain

0.12

MetaRNN

Uncertain

0.68

D;D;D;D

MetaSVM

Uncertain

0.13

MutationAssessor

Benign

0.97

L;L;.;.

PhyloP100

6.0

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-2.0

N;N;.;N

REVEL

Uncertain

0.53

Sift

Benign

0.14

T;T;.;T

Sift4G

Benign

0.74

T;T;T;T

Polyphen

0.97

D;P;P;P

Vest4

0.86

MVP

0.90

ClinPred

0.31

GERP RS

4.7

Varity_R

0.35

gMVP

0.36

Mutation Taster

=23/77

disease causing

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

9-99828440-T-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over