5-143403416-G-T

Variant names:

• chr5-143403416-G-T
• rs10482612
• NM_000176.3:c.-219C>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BS1 BS2

The NM_000176.3(NR3C1):​c.-219C>A variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000207 in 982,934 control chromosomes in the GnomAD database, including 1 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 0.00063 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: NR3C1 NM_000176.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0860
• Publications: 4 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000628 (94/149730) while in subpopulation EAS AF = 0.0174 (87/4988). AF 95% confidence interval is 0.0145. There are 1 homozygotes in GnomAd4. There are 58 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 94 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000176.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR3C1	NM_000176.3	MANE Select	c.-219C>A		5_prime_UTR_premature_start_codon_gain	Exon 1 of 9	NP_000167.1
	NR3C1	NM_000176.3	MANE Select	c.-219C>A		5_prime_UTR	Exon 1 of 9	NP_000167.1
	NR3C1	NM_001024094.2		c.-219C>A		5_prime_UTR_premature_start_codon_gain	Exon 1 of 9	NP_001019265.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR3C1	ENST00000394464.7	TSL:1 MANE Select	c.-219C>A		5_prime_UTR_premature_start_codon_gain	Exon 1 of 9	ENSP00000377977.2
	NR3C1	ENST00000231509.7	TSL:1	c.-219C>A		5_prime_UTR_premature_start_codon_gain	Exon 1 of 9	ENSP00000231509.3
	NR3C1	ENST00000394464.7	TSL:1 MANE Select	c.-219C>A		5_prime_UTR	Exon 1 of 9	ENSP00000377977.2

Frequencies

GnomAD3 genomes AF: 0.000628 AC: 94 AN: 149622 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000665

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0174

Gnomad SAS AF: 0.00128

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000131 AC: 109 AN: 833204 Hom.: 0 Cov.: 30 AF XY: 0.000130 AC XY: 50 AN XY: 384790

African (AFR) AF: 0.00 AC: 0 AN: 15786

American (AMR) AF: 0.00 AC: 0 AN: 984

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5152

East Asian (EAS) AF: 0.0171 AC: 62 AN: 3636

South Asian (SAS) AF: 0.000851 AC: 14 AN: 16460

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 278

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1622

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 761982

Other (OTH) AF: 0.00121 AC: 33 AN: 27304

GnomAD4 genome AF: 0.000628 AC: 94 AN: 149730 Hom.: 1 Cov.: 32 AF XY: 0.000795 AC XY: 58 AN XY: 72984

African (AFR) AF: 0.00 AC: 0 AN: 40706

American (AMR) AF: 0.0000665 AC: 1 AN: 15048

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3462

East Asian (EAS) AF: 0.0174 AC: 87 AN: 4988

South Asian (SAS) AF: 0.00128 AC: 6 AN: 4672

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10222

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67384

Other (OTH) AF: 0.00 AC: 0 AN: 2052

Alfa AF: 0.000201 Hom.: 1

Bravo AF: 0.000725

Asia WGS AF: 0.00462 AC: 16 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	10
DANN	Benign	0.89
PhyloP100		-0.086
PromoterAI		-0.0042	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs10482612; hg19: chr5-142782981;