9-99833356-C-T

Position:

• chr9-99833356-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006981.4(NR4A3):​c.1156C>T​(p.Pro386Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: NR4A3 NM_006981.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.08

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.109826475).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NR4A3	NM_006981.4	c.1156C>T	p.Pro386Ser	missense_variant	5/8	ENST00000395097.7
NR4A3	NM_173200.3	c.1189C>T	p.Pro397Ser	missense_variant	6/9
NR4A3	NM_173199.4	c.1156C>T	p.Pro386Ser	missense_variant	5/5
NR4A3	XM_017015162.2	c.1156C>T	p.Pro386Ser	missense_variant	6/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NR4A3	ENST00000395097.7	c.1156C>T	p.Pro386Ser	missense_variant	5/8	1	NM_006981.4	P1
STX17-DT	ENST00000655615.1	n.268+5630G>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 09, 2021

The c.1189C>T (p.P397S) alteration is located in exon 6 (coding exon 4) of the NR4A3 gene. This alteration results from a C to T substitution at nucleotide position 1189, causing the proline (P) at amino acid position 397 to be replaced by a serine (S). 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	0.080
BayesDel_addAF	Benign	-0.061	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	.;T;.;.
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.84	T;T;T;.
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.11	T;T;T;T
MetaSVM	Benign	-0.36	T
MutationAssessor	Benign	0.55	N;N;.;.
MutationTaster	Benign	0.93	D;D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.5	N;N;.;N
REVEL	Benign	0.16
Sift	Benign	0.051	T;T;.;T
Sift4G	Benign	0.57	T;T;T;T
Polyphen		0.011	B;B;B;B
Vest4		0.14
MutPred		0.24		Gain of phosphorylation at P386 (P = 0.0078);Gain of phosphorylation at P386 (P = 0.0078);.;.;
MVP		0.70
ClinPred		0.17	T
GERP RS		2.7
Varity_R		0.071
gMVP		0.49

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-102595638;