rs12803

chr2-156325413-A-Cchr2-156325413-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_006186.4(NR4A2):c.*331T>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.442 in 363,146 control chromosomes in the GnomAD database, including 39,694 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.39 (14020 hom., cov: 32)
  • Exomes 𝑓: 0.48 (25674 hom.)
• Consequence: NR4A2 NM_006186.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.90

Genes affected

NR4A2 (HGNC:7981): (nuclear receptor subfamily 4 group A member 2) This gene encodes a member of the steroid-thyroid hormone-retinoid receptor superfamily. The encoded protein may act as a transcription factor. Mutations in this gene have been associated with disorders related to dopaminergic dysfunction, including Parkinson disease, schizophernia, and manic depression. Misregulation of this gene may be associated with rheumatoid arthritis. Alternatively spliced transcript variants have been described, but their biological validity has not been determined. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 2-156325413-A-C is Benign according to our data. Variant chr2-156325413-A-C is described in ClinVar as [Benign]. Clinvar id is 331655.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.532 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NR4A2	NM_006186.4	c.*331T>G		3_prime_UTR_variant	8/8	ENST00000339562.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NR4A2	ENST00000339562.9	c.*331T>G		3_prime_UTR_variant	8/8	1	NM_006186.4	P1

Frequencies

GnomAD3 genomes AF: 0.394 AC: 59795 AN: 151894 Hom.: 14022 Cov.: 32

Gnomad AFR AF: 0.160

Gnomad AMI AF: 0.503

Gnomad AMR AF: 0.317

Gnomad ASJ AF: 0.476

Gnomad EAS AF: 0.176

Gnomad SAS AF: 0.435

Gnomad FIN AF: 0.552

Gnomad MID AF: 0.408

Gnomad NFE AF: 0.536

Gnomad OTH AF: 0.402

GnomAD4 exome AF: 0.478 AC: 100910 AN: 211132 Hom.: 25674 Cov.: 0 AF XY: 0.473 AC XY: 54439 AN XY: 115038

Gnomad4 AFR exome AF: 0.152

Gnomad4 AMR exome AF: 0.283

Gnomad4 ASJ exome AF: 0.475

Gnomad4 EAS exome AF: 0.170

Gnomad4 SAS exome AF: 0.442

Gnomad4 FIN exome AF: 0.559

Gnomad4 NFE exome AF: 0.539

Gnomad4 OTH exome AF: 0.483

GnomAD4 genome AF: 0.393 AC: 59779 AN: 152014 Hom.: 14020 Cov.: 32 AF XY: 0.389 AC XY: 28903 AN XY: 74270

Gnomad4 AFR AF: 0.159

Gnomad4 AMR AF: 0.317

Gnomad4 ASJ AF: 0.476

Gnomad4 EAS AF: 0.177

Gnomad4 SAS AF: 0.436

Gnomad4 FIN AF: 0.552

Gnomad4 NFE AF: 0.536

Gnomad4 OTH AF: 0.399

Alfa AF: 0.490 Hom.: 18229

Bravo AF: 0.358

Asia WGS AF: 0.290 AC: 1009 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Parkinson disease, late-onset Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
Cadd	Benign	13
Dann	Benign	0.84

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: rs12803; hg19: chr2-157181925; COSMIC: COSV59894704; COSMIC: COSV59894704;