rs4912910

Variant names:

• chr5-143427325-A-G
• rs4912910
• ENST00000504572.5:c.-14+6394T>C

Your query was ambiguous. Multiple possible variants found:

• chr5-143427325-A-G
• chr5-143427325-A-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001364183.2(NR3C1):​c.-14+6394T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.564 in 151,824 control chromosomes in the GnomAD database, including 25,428 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.56 (25428 hom., cov: 31)
• Consequence: NR3C1 NM_001364183.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0750
• Publications: 15 publications found

Genes affected

NR3C1 (HGNC:7978): (nuclear receptor subfamily 3 group C member 1) This gene encodes glucocorticoid receptor, which can function both as a transcription factor that binds to glucocorticoid response elements in the promoters of glucocorticoid responsive genes to activate their transcription, and as a regulator of other transcription factors. This receptor is typically found in the cytoplasm, but upon ligand binding, is transported into the nucleus. It is involved in inflammatory responses, cellular proliferation, and differentiation in target tissues. Mutations in this gene are associated with generalized glucocorticoid resistance. Alternative splicing of this gene results in transcript variants encoding either the same or different isoforms. Additional isoforms resulting from the use of alternate in-frame translation initiation sites have also been described, and shown to be functional, displaying diverse cytoplasm-to-nucleus trafficking patterns and distinct transcriptional activities (PMID:15866175). [provided by RefSeq, Feb 2011]

NR3C1 Gene-Disease associations (from GenCC):

• glucocorticoid resistance

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Laboratory for Molecular Medicine, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.66 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001364183.2. 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
	NR3C1	NM_001364183.2		c.-14+6394T>C		intron	N/A	NP_001351112.1
	NR3C1	NM_001018074.1		c.-14+7879T>C		intron	N/A	NP_001018084.1
	NR3C1	NM_001018075.1		c.-14+7976T>C		intron	N/A	NP_001018085.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR3C1	ENST00000504572.5	TSL:1	c.-14+6394T>C		intron	N/A	ENSP00000422518.1
	NR3C1	ENST00000870492.1		c.-14+7207T>C		intron	N/A	ENSP00000540551.1
	NR3C1	ENST00000343796.6	TSL:5	c.-14+7207T>C		intron	N/A	ENSP00000343205.2

Frequencies

GnomAD3 genomes AF: 0.564 AC: 85574 AN: 151706 Hom.: 25432 Cov.: 31

Gnomad AFR AF: 0.360

Gnomad AMI AF: 0.632

Gnomad AMR AF: 0.574

Gnomad ASJ AF: 0.730

Gnomad EAS AF: 0.561

Gnomad SAS AF: 0.577

Gnomad FIN AF: 0.626

Gnomad MID AF: 0.611

Gnomad NFE AF: 0.665

Gnomad OTH AF: 0.584

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.564 AC: 85595 AN: 151824 Hom.: 25428 Cov.: 31 AF XY: 0.563 AC XY: 41753 AN XY: 74180

African (AFR) AF: 0.359 AC: 14870 AN: 41366

American (AMR) AF: 0.574 AC: 8757 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.730 AC: 2532 AN: 3470

East Asian (EAS) AF: 0.561 AC: 2890 AN: 5154

South Asian (SAS) AF: 0.578 AC: 2779 AN: 4812

European-Finnish (FIN) AF: 0.626 AC: 6573 AN: 10502

Middle Eastern (MID) AF: 0.595 AC: 175 AN: 294

European-Non Finnish (NFE) AF: 0.665 AC: 45210 AN: 67958

Other (OTH) AF: 0.587 AC: 1233 AN: 2102

Alfa AF: 0.624 Hom.: 85486

Bravo AF: 0.549

Asia WGS AF: 0.544 AC: 1895 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.4
DANN	Benign	0.66
PhyloP100		-0.075
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs4912910; hg19: chr5-142806890; COSMIC: COSV59429828;