5-143403448-A-G

Variant names:

• chr5-143403448-A-G
• rs10482611
• NM_000176.3:c.-251T>C

Variant summary

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

The NM_000176.3(NR3C1):​c.-251T>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.996 in 985,312 control chromosomes in the GnomAD database, including 488,693 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 0.98 (73262 hom., cov: 33)
  • Exomes 𝑓: 1.0 (415431 hom.)
• Consequence: NR3C1 NM_000176.3 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.307
• Publications: 2 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=-0.84).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

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.-251T>C		5_prime_UTR	Exon 1 of 9	NP_000167.1
	NR3C1	NM_001024094.2		c.-251T>C		5_prime_UTR	Exon 1 of 9	NP_001019265.1
	NR3C1	NM_001204258.2		c.-329T>C		5_prime_UTR	Exon 1 of 9	NP_001191187.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR3C1	ENST00000394464.7	TSL:1 MANE Select	c.-251T>C		5_prime_UTR	Exon 1 of 9	ENSP00000377977.2
	NR3C1	ENST00000231509.7	TSL:1	c.-251T>C		5_prime_UTR	Exon 1 of 9	ENSP00000231509.3
	NR3C1	ENST00000504572.5	TSL:1	c.-13-2596T>C		intron	N/A	ENSP00000422518.1

Frequencies

GnomAD3 genomes AF: 0.981 AC: 149097 AN: 151962 Hom.: 73212 Cov.: 33

Gnomad AFR AF: 0.934

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.995

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.990

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.987

GnomAD4 exome AF: 0.999 AC: 832013 AN: 833242 Hom.: 415431 Cov.: 62 AF XY: 0.999 AC XY: 384288 AN XY: 384818

African (AFR) AF: 0.933 AC: 14731 AN: 15786

American (AMR) AF: 1.00 AC: 986 AN: 986

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 5154 AN: 5154

East Asian (EAS) AF: 1.00 AC: 3640 AN: 3640

South Asian (SAS) AF: 1.00 AC: 16459 AN: 16460

European-Finnish (FIN) AF: 1.00 AC: 280 AN: 280

Middle Eastern (MID) AF: 0.996 AC: 1615 AN: 1622

European-Non Finnish (NFE) AF: 1.00 AC: 761953 AN: 762012

Other (OTH) AF: 0.996 AC: 27195 AN: 27302

GnomAD4 genome AF: 0.981 AC: 149202 AN: 152070 Hom.: 73262 Cov.: 33 AF XY: 0.982 AC XY: 72979 AN XY: 74326

African (AFR) AF: 0.934 AC: 38730 AN: 41466

American (AMR) AF: 0.995 AC: 15223 AN: 15306

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3472 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5106 AN: 5106

South Asian (SAS) AF: 1.00 AC: 4831 AN: 4832

European-Finnish (FIN) AF: 1.00 AC: 10598 AN: 10598

Middle Eastern (MID) AF: 0.990 AC: 289 AN: 292

European-Non Finnish (NFE) AF: 1.00 AC: 67953 AN: 67970

Other (OTH) AF: 0.987 AC: 2088 AN: 2116

Alfa AF: 0.990 Hom.: 9082

Bravo AF: 0.979

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	5.9
DANN	Benign	0.35
PhyloP100		0.31
PromoterAI		-0.063	Neutral
Mutation Taster		=300/0	polymorphism (auto)

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: rs10482611; hg19: chr5-142783013;