chr9-99863739-G-C

Position:

• chr9-99863739-G-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Moderate BP6_Moderate BS2

The NM_006981.4(NR4A3):​c.1753G>C​(p.Gly585Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000576 in 1,613,748 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000055 (1 hom.)
• Consequence: NR4A3 NM_006981.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.837

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]

STX17-DT (HGNC:51174): (STX17 divergent transcript)

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.17031932).
• BP6: Variant 9-99863739-G-C is Benign according to our data. Variant chr9-99863739-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 2381811.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NR4A3	NM_006981.4	c.1753G>C	p.Gly585Arg	missense_variant	8/8	ENST00000395097.7
NR4A3	NM_173200.3	c.1786G>C	p.Gly596Arg	missense_variant	9/9
NR4A3	XM_017015162.2	c.1753G>C	p.Gly585Arg	missense_variant	9/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NR4A3	ENST00000395097.7	c.1753G>C	p.Gly585Arg	missense_variant	8/8	1	NM_006981.4	P1
STX17-DT	ENST00000655615.1	n.179-24664C>G		intron_variant, non_coding_transcript_variant
NR4A3	ENST00000330847.1	c.1786G>C	p.Gly596Arg	missense_variant	7/7	5
NR4A3	ENST00000618101.4	c.1786G>C	p.Gly596Arg	missense_variant	9/9	5

Frequencies

GnomAD3 genomes AF: 0.0000855 AC: 13 AN: 152062 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.000132

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.0000798 AC: 20 AN: 250662 Hom.: 0 AF XY: 0.0000960 AC XY: 13 AN XY: 135442

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000869

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000115

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000547 AC: 80 AN: 1461686 Hom.: 1 Cov.: 32 AF XY: 0.0000646 AC XY: 47 AN XY: 727136

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.000191

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000531

Gnomad4 OTH exome AF: 0.0000662

GnomAD4 genome AF: 0.0000855 AC: 13 AN: 152062 Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8 AN XY: 74272

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.000957

Alfa AF: 0.0000637 Hom.: 0

Bravo AF: 0.0000604

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.0000824 AC: 10

EpiCase AF: 0.000273

EpiControl AF: 0.000178

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 04, 2022

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	0.12
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	15
DANN	Benign	0.92
DEOGEN2	Pathogenic	0.91	D;.;.
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.64
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.89	D;D;.
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.17	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.1	M;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.35	T
PROVEAN	Pathogenic	-5.1	D;.;D
REVEL	Benign	0.20
Sift	Benign	0.073	T;.;T
Sift4G	Uncertain	0.059	T;T;T
Polyphen		0.022	B;B;B
Vest4		0.10
MVP		0.44
ClinPred		0.41	T
GERP RS		-0.79
Varity_R		0.47
gMVP		0.63

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

Other links and lift over

dbSNP: rs201429822; hg19: chr9-102626021;