Variant 9-99828656-C-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_006981.4(NR4A3):c.614C>G(p.Pro205Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000198 in 151,548 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. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 31)

Consequence

NR4A3
NM_006981.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.36

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 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3611471).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
NR4A3	NM_006981.4 linkuse as main transcript	c.614C>G	p.Pro205Arg	missense_variant	3/8	ENST00000395097.7
NR4A3	NM_173200.3 linkuse as main transcript	c.647C>G	p.Pro216Arg	missense_variant	4/9
NR4A3	NM_173199.4 linkuse as main transcript	c.614C>G	p.Pro205Arg	missense_variant	3/5
NR4A3	XM_017015162.2 linkuse as main transcript	c.614C>G	p.Pro205Arg	missense_variant	4/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NR4A3	ENST00000395097.7 linkuse as main transcript	c.614C>G	p.Pro205Arg	missense_variant	3/8	1	NM_006981.4	P1	Q92570-1
STX17-DT	ENST00000655615.1 linkuse as main transcript	n.268+10330G>C		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.0000198

AC:

AN:

151548

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000725

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

AF:

0.0000198

AC:

AN:

151548

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

AN XY:

74004

show subpopulations

Gnomad4 AFR

AF:

0.0000725

Gnomad4 AMR

AF:

0.00

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:

0.00

Bravo

AF:

0.0000113

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 04, 2023

The c.647C>G (p.P216R) 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 647, causing the proline (P) at amino acid position 216 to be replaced by an arginine (R). 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

0.13

BayesDel_addAF

Uncertain

0.025

BayesDel_noAF

Benign

-0.20

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.28

.;T;.;.

Eigen

Benign

-0.080

Eigen_PC

Benign

0.023

FATHMM_MKL

Benign

0.51

LIST_S2

Benign

0.72

T;T;T;.

M_CAP

Pathogenic

0.97

MetaRNN

Benign

0.36

T;T;T;T

MetaSVM

Benign

-0.33

MutationAssessor

Benign

0.0

N;N;.;.

MutationTaster

Benign

0.93

D;D;D

PrimateAI

Pathogenic

0.92

PROVEAN

Benign

-0.88

N;N;.;N

REVEL

Benign

0.27

Sift

Benign

0.091

T;T;.;T

Sift4G

Benign

0.59

T;T;T;T

Polyphen

0.61

P;P;P;P

Vest4

0.30

MutPred

0.31

Gain of methylation at P205 (P = 0.0098);Gain of methylation at P205 (P = 0.0098);.;.;

MVP

0.79

ClinPred

0.23

GERP RS

4.0

Varity_R

0.085

gMVP

0.41

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