12-52057151-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_173157.3(NR4A1):c.1253G>A(p.Arg418His) variant causes a missense change. The variant allele was found at a frequency of 0.00137 in 1,614,064 control chromosomes in the GnomAD database, including 52 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0026 (10 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (42 hom.)
• Consequence: NR4A1 NM_173157.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 5.83

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008199543).
• BP6: Variant 12-52057151-G-A is Benign according to our data. Variant chr12-52057151-G-A is described in ClinVar as [Benign]. Clinvar id is 778444.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00261 (397/152326) while in subpopulation AMR AF= 0.0254 (388/15296). AF 95% confidence interval is 0.0233. There are 10 homozygotes in gnomad4. There are 227 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 395 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NR4A1	NM_173157.3	c.1253G>A	p.Arg418His	missense_variant	5/7	ENST00000394825.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NR4A1	ENST00000394825.6	c.1253G>A	p.Arg418His	missense_variant	5/7	1	NM_173157.3	P1

Frequencies

GnomAD3 genomes AF: 0.00260 AC: 395 AN: 152208 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0253

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: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00565 AC: 1418 AN: 250836 Hom.: 35 AF XY: 0.00428 AC XY: 581 AN XY: 135618

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.0401

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00523

GnomAD4 exome AF: 0.00124 AC: 1810 AN: 1461738 Hom.: 42 Cov.: 32 AF XY: 0.00102 AC XY: 739 AN XY: 727146

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.0385

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000288

Gnomad4 OTH exome AF: 0.000878

GnomAD4 genome AF: 0.00261 AC: 397 AN: 152326 Hom.: 10 Cov.: 32 AF XY: 0.00305 AC XY: 227 AN XY: 74478

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.0254

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000121 Hom.: 0

Bravo AF: 0.00429

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00390 AC: 474

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Pathogenic	0.31
Cadd	Pathogenic	30
Dann	Pathogenic	1.0
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Benign	0.42	N
MetaRNN	Benign	0.0082	T
MutationTaster	Benign	1.0	D;D;D;D;D;D
PROVEAN	Uncertain	-4.0	D
MVP		0.66
ClinPred		0.14	T
GERP RS		5.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs137975531; hg19: chr12-52450935;