9-99828486-C-A

Position:

chr9-99828486-C-A

Variant summary

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

The NM_006981.4(NR4A3):c.444C>A(p.Phe148Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000253 in 1,577,974 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: 𝑓 0.000033 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

NR4A3
NM_006981.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.35

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=0.07321808).

BS2

High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NR4A3	NM_006981.4 linkuse as main transcript	c.444C>A	p.Phe148Leu	missense_variant	3/8	ENST00000395097.7	NP_008912.2	Q92570-1A0A024R168
NR4A3	NM_173200.3 linkuse as main transcript	c.477C>A	p.Phe159Leu	missense_variant	4/9		NP_775292.1	Q92570-3
NR4A3	NM_173199.4 linkuse as main transcript	c.444C>A	p.Phe148Leu	missense_variant	3/5		NP_775291.1	Q92570-2
NR4A3	XM_017015162.2 linkuse as main transcript	c.444C>A	p.Phe148Leu	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.444C>A	p.Phe148Leu	missense_variant	3/8	1	NM_006981.4	ENSP00000378531.2		Q92570-1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

151868

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000972

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000630

AC:

AN:

206388

Hom.:

AF XY:

0.0000533

AC XY:

AN XY:

112614

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000722

Gnomad SAS exome

AF:

0.0000415

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000245

AC:

AN:

1426106

Hom.:

Cov.:

AF XY:

0.0000198

AC XY:

AN XY:

706392

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000432

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.12e-7

Gnomad4 OTH exome

AF:

0.000289

GnomAD4 genome

AF:

0.0000329

AC:

AN:

151868

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74204

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000972

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.0000604

ExAC

AF:

0.0000586

AC:

Asia WGS

AF:

0.000867

AC:

AN:

3476

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

Jul 16, 2024

The c.477C>A (p.F159L) alteration is located in exon 4 (coding exon 2) of the NR4A3 gene. This alteration results from a C to A substitution at nucleotide position 477, causing the phenylalanine (F) at amino acid position 159 to be replaced by a leucine (L). 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

Uncertain

0.52

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.11

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.62

.;D;.;.

Eigen

Benign

-0.28

Eigen_PC

Benign

-0.15

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.72

T;T;T;.

M_CAP

Uncertain

0.24

MetaRNN

Benign

0.073

T;T;T;T

MetaSVM

Benign

-0.46

MutationAssessor

Benign

1.3

L;L;.;.

PrimateAI

Uncertain

0.76

PROVEAN

Uncertain

-2.9

D;D;.;D

REVEL

Uncertain

0.38

Sift

Benign

0.055

T;T;.;T

Sift4G

Benign

0.13

T;T;T;T

Polyphen

0.055

B;B;B;B

Vest4

0.24

MutPred

0.28

Gain of glycosylation at P149 (P = 0.1628);Gain of glycosylation at P149 (P = 0.1628);.;.;

MVP

0.82

ClinPred

0.19

GERP RS

2.8

Varity_R

0.27

gMVP

0.21

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