9-99828802-C-G

Position:

chr9-99828802-C-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_006981.4(NR4A3):c.760C>G(p.Leu254Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000258 in 1,471,144 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000024 ( 0 hom. )

Consequence

NR4A3
NM_006981.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.93

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:

STX17-DT (HGNC:):

STX17-DT links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.26019996).

BS2

High AC in GnomAd4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NR4A3	NM_006981.4 linkuse as main transcript	c.760C>G	p.Leu254Val	missense_variant	3/8	ENST00000395097.7	NP_008912.2	Q92570-1A0A024R168
NR4A3	NM_173200.3 linkuse as main transcript	c.793C>G	p.Leu265Val	missense_variant	4/9		NP_775292.1	Q92570-3
NR4A3	NM_173199.4 linkuse as main transcript	c.760C>G	p.Leu254Val	missense_variant	3/5		NP_775291.1	Q92570-2
NR4A3	XM_017015162.2 linkuse as main transcript	c.760C>G	p.Leu254Val	missense_variant	4/9		XP_016870651.1	Q92570-1A0A024R168

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NR4A3	ENST00000395097.7 linkuse as main transcript	c.760C>G	p.Leu254Val	missense_variant	3/8	1	NM_006981.4	ENSP00000378531.2		Q92570-1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152116

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

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:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000127

AC:

AN:

78896

Hom.:

AF XY:

0.000133

AC XY:

AN XY:

45122

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000564

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000356

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000235

AC:

AN:

1318910

Hom.:

Cov.:

AF XY:

0.0000293

AC XY:

AN XY:

649212

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000580

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000124

Gnomad4 OTH exome

AF:

0.0000367

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152234

Hom.:

Cov.:

AF XY:

0.0000537

AC XY:

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000112

Hom.:

Bravo

AF:

0.0000680

ExAC

AF:

0.0000148

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 08, 2024

The c.793C>G (p.L265V) alteration is located in exon 4 (coding exon 2) of the NR4A3 gene. This alteration results from a C to G substitution at nucleotide position 793, causing the leucine (L) at amino acid position 265 to be replaced by a valine (V). 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

Benign

0.077

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.25

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.26

.;T;.;.

Eigen

Benign

0.015

Eigen_PC

Benign

0.017

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.73

T;T;T;.

M_CAP

Pathogenic

0.39

MetaRNN

Benign

0.26

T;T;T;T

MetaSVM

Uncertain

-0.085

MutationAssessor

Benign

0.97

L;L;.;.

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-1.1

N;N;.;N

REVEL

Uncertain

0.30

Sift

Benign

0.17

T;T;.;T

Sift4G

Benign

0.22

T;T;T;T

Polyphen

0.94

P;B;P;P

Vest4

0.33

MVP

0.81

ClinPred

0.084

GERP RS

2.4

Varity_R

0.096

gMVP

0.42

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over