12-52058831-C-A

Variant names:

• chr12-52058831-C-A
• rs771251157
• NM_173157.3:c.1684C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_173157.3(NR4A1):​c.1684C>A​(p.Leu562Met) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L562V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NR4A1 NM_173157.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.14
• Publications: 4 publications found

Genes affected

NR4A1 (HGNC:7980): (nuclear receptor subfamily 4 group A member 1) This gene encodes a member of the steroid-thyroid hormone-retinoid receptor superfamily. Expression is induced by phytohemagglutinin in human lymphocytes and by serum stimulation of arrested fibroblasts. The encoded protein acts as a nuclear transcription factor. Translocation of the protein from the nucleus to mitochondria induces apoptosis. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2011]

NR4A1AS (HGNC:54409): (NR4A1 antisense RNA)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173157.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR4A1	NM_173157.3	MANE Select	c.1684C>A	p.Leu562Met	missense	Exon 7 of 7	NP_775180.1	P22736-1
	NR4A1	NM_001202234.2		c.1846C>A	p.Leu616Met	missense	Exon 8 of 8	NP_001189163.1	F5GXF0
	NR4A1	NM_001202233.2		c.1723C>A	p.Leu575Met	missense	Exon 8 of 8	NP_001189162.1	P22736-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR4A1	ENST00000394825.6	TSL:1 MANE Select	c.1684C>A	p.Leu562Met	missense	Exon 7 of 7	ENSP00000378302.1	P22736-1
	NR4A1	ENST00000243050.5	TSL:1	c.1684C>A	p.Leu562Met	missense	Exon 8 of 8	ENSP00000243050.1	P22736-1
	NR4A1	ENST00000550557.1	TSL:1	n.4165C>A		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000645 AC: 16 AN: 248186 AF XY: 0.0000594

Gnomad AFR exome AF: 0.000187

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000110

Gnomad FIN exome AF: 0.000189

Gnomad NFE exome AF: 0.0000537

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000274 AC: 4 AN: 1460918 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726810

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33462

American (AMR) AF: 0.00 AC: 0 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39668

South Asian (SAS) AF: 0.00 AC: 0 AN: 86222

European-Finnish (FIN) AF: 0.0000379 AC: 2 AN: 52828

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5706

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111866

Other (OTH) AF: 0.00 AC: 0 AN: 60344

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000132963), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ExAC AF: 0.000198 AC: 24

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D
Eigen	Pathogenic	0.79
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Benign	0.37	N
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.15	D
MetaRNN	Uncertain	0.65	D
MetaSVM	Uncertain	0.45	D
MutationAssessor	Pathogenic	4.1	H
PhyloP100		4.1
PrimateAI	Pathogenic	0.87	D
PROVEAN	Benign	-1.8	N
REVEL	Pathogenic	0.67
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.73
MVP		0.73
MPC		1.1
ClinPred		0.94	D
GERP RS		4.2
Varity_R		0.87
gMVP		0.58
Mutation Taster		=65/35	polymorphism

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

Other links and lift over

dbSNP: rs771251157; hg19: chr12-52452615; COSMIC: COSV54479710; COSMIC: COSV54479710;