12-52056023-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_173157.3(NR4A1):c.877-7C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000164 in 1,481,914 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00027 (0 hom., cov: 28)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: NR4A1 NM_173157.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00002558
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.338

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 12-52056023-C-T is Benign according to our data. Variant chr12-52056023-C-T is described in ClinVar as [Benign]. Clinvar id is 779948.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 41 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NR4A1	NM_173157.3	c.877-7C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000394825.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NR4A1	ENST00000394825.6	c.877-7C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_173157.3	P1

Frequencies

GnomAD3 genomes AF: 0.000270 AC: 41 AN: 151780 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00620

Gnomad SAS AF: 0.000625

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000295

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000383 AC: 64 AN: 167042 Hom.: 0 AF XY: 0.000367 AC XY: 33 AN XY: 89826

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00511

Gnomad SAS exome AF: 0.000132

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000244

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000152 AC: 202 AN: 1330014 Hom.: 0 Cov.: 32 AF XY: 0.000140 AC XY: 91 AN XY: 651258

Gnomad4 AFR exome AF: 0.0000344

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00262

Gnomad4 SAS exome AF: 0.000184

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000766

Gnomad4 OTH exome AF: 0.000350

GnomAD4 genome AF: 0.000270 AC: 41 AN: 151900 Hom.: 0 Cov.: 28 AF XY: 0.000283 AC XY: 21 AN XY: 74272

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00621

Gnomad4 SAS AF: 0.000626

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000295

Gnomad4 OTH AF: 0.00

Bravo AF: 0.000204

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
BayesDel_noAF	Benign	-0.69
Cadd	Benign	11
Dann	Benign	0.85

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000026
dbscSNV1_RF	Benign	0.0
SpliceAI score (max)		0.020		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: rs201901500; hg19: chr12-52449807; COSMIC: COSV54482506; COSMIC: COSV54482506;