chr9-99828378-T-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_006981.4(NR4A3):c.336T>G(p.His112Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000546 in 1,594,128 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000080 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000052 ( 0 hom. )

Consequence

NR4A3
NM_006981.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.437

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: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.024261504).

BP6

Variant 9-99828378-T-G is Benign according to our data. Variant chr9-99828378-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 3880943.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAd4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR4A3	NM_006981.4 link	c.336T>G	p.His112Gln	missense_variant	Exon 3 of 8	ENST00000395097.7	NP_008912.2	Q92570-1A0A024R168
NR4A3	NM_173200.3 link	c.369T>G	p.His123Gln	missense_variant	Exon 4 of 9		NP_775292.1	Q92570-3
NR4A3	NM_173199.4 link	c.336T>G	p.His112Gln	missense_variant	Exon 3 of 5		NP_775291.1	Q92570-2
NR4A3	XM_017015162.2 link	c.336T>G	p.His112Gln	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.336T>G	p.His112Gln	missense_variant	Exon 3 of 8	1	NM_006981.4	ENSP00000378531.2		Q92570-1

Frequencies

GnomAD3 genomes

AF:

0.0000795

AC:

AN:

150926

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000122

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000658

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:

0.0000886

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000754

AC:

AN:

225440

AF XY:

0.0000742

show subpopulations

Gnomad AFR exome

AF:

0.0000642

Gnomad AMR exome

AF:

0.000149

Gnomad ASJ exome

AF:

0.000129

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000702

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000520

AC:

AN:

1443202

Hom.:

Cov.:

AF XY:

0.0000671

AC XY:

AN XY:

715836

show subpopulations

African (AFR)

AF:

0.0000300

AC:

AN:

33366

American (AMR)

AF:

0.000137

AC:

AN:

43934

Ashkenazi Jewish (ASJ)

AF:

0.0000815

AC:

AN:

24530

East Asian (EAS)

AF:

0.0000757

AC:

AN:

39622

South Asian (SAS)

AF:

0.0000608

AC:

AN:

82206

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51152

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5680

European-Non Finnish (NFE)

AF:

0.0000517

AC:

AN:

1102980

Other (OTH)

AF:

0.0000167

AC:

AN:

59732

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.460

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000795

AC:

AN:

150926

Hom.:

Cov.:

AF XY:

0.0000678

AC XY:

AN XY:

73706

show subpopulations

African (AFR)

AF:

0.000122

AC:

AN:

40974

American (AMR)

AF:

0.0000658

AC:

AN:

15196

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3454

East Asian (EAS)

AF:

0.00

AC:

AN:

5102

South Asian (SAS)

AF:

0.00

AC:

AN:

4768

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10444

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000886

AC:

AN:

67692

Other (OTH)

AF:

0.00

AC:

AN:

2072

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.0000744

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Dec 30, 2024

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.38

CADD

Benign

1.6

(source)

DANN

Benign

0.45

DEOGEN2

Benign

0.24

.;T;.;.

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.014

LIST_S2

Benign

0.45

T;T;T;.

M_CAP

Benign

0.056

MetaRNN

Benign

0.024

T;T;T;T

MetaSVM

Benign

-0.57

MutationAssessor

Benign

-0.55

N;N;.;.

PhyloP100

-0.44

PrimateAI

Benign

0.37

PROVEAN

Benign

0.33

N;N;.;N

REVEL

Benign

0.23

Sift

Benign

1.0

T;T;.;T

Sift4G

Benign

0.32

T;T;T;T

Polyphen

0.0

B;B;B;B

Vest4

0.22

MutPred

0.17

Gain of glycosylation at P115 (P = 0.0814);Gain of glycosylation at P115 (P = 0.0814);.;.;

MVP

0.34

ClinPred

0.016

GERP RS

-0.073

Varity_R

0.039

gMVP

0.098

Mutation Taster

=99/1

polymorphism

(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.

chr9-99828378-T-G

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