Variant chr9-99863668-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_006981.4(NR4A3):c.1682A>C(p.Lys561Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,698 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

NR4A3
NM_006981.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.39

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:51174): (STX17 divergent transcript)

STX17-DT links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
NR4A3	NM_006981.4 linkuse as main transcript	c.1682A>C	p.Lys561Thr	missense_variant	8/8	ENST00000395097.7
NR4A3	NM_173200.3 linkuse as main transcript	c.1715A>C	p.Lys572Thr	missense_variant	9/9
NR4A3	XM_017015162.2 linkuse as main transcript	c.1682A>C	p.Lys561Thr	missense_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NR4A3	ENST00000395097.7 linkuse as main transcript	c.1682A>C	p.Lys561Thr	missense_variant	8/8	1	NM_006981.4	P1	Q92570-1
STX17-DT	ENST00000655615.1 linkuse as main transcript	n.179-24593T>G		intron_variant, non_coding_transcript_variant
NR4A3	ENST00000330847.1 linkuse as main transcript	c.1715A>C	p.Lys572Thr	missense_variant	7/7	5			Q92570-3
NR4A3	ENST00000618101.4 linkuse as main transcript	c.1715A>C	p.Lys572Thr	missense_variant	9/9	5			Q92570-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250660

Hom.:

AF XY:

0.00000738

AC XY:

AN XY:

135430

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000545

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461698

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727148

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

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

May 03, 2023

The c.1715A>C (p.K572T) alteration is located in exon 9 (coding exon 7) of the NR4A3 gene. This alteration results from a A to C substitution at nucleotide position 1715, causing the lysine (K) at amino acid position 572 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

Benign

0.25

BayesDel_addAF

Benign

-0.049

BayesDel_noAF

Benign

-0.14

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.89

D;.;.

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.54

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.89

D;D;.

M_CAP

Benign

0.035

MetaRNN

Uncertain

0.64

D;D;D

MetaSVM

Benign

-0.51

MutationAssessor

Uncertain

2.1

M;.;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.75

PROVEAN

Pathogenic

-4.5

D;.;D

REVEL

Uncertain

0.33

Sift

Uncertain

0.0050

D;.;D

Sift4G

Uncertain

0.0050

D;D;D

Polyphen

0.94

P;P;P

Vest4

0.57

MutPred

0.61

Loss of ubiquitination at K561 (P = 0.0192);.;.;

MVP

0.73

ClinPred

0.94

GERP RS

4.8

Varity_R

0.49

gMVP

0.62

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