5-143403006-T-G

Variant names:

• chr5-143403006-T-G
• rs4406157
• NM_000176.3:c.-14+205A>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.-14+205A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.981 in 148,144 control chromosomes in the GnomAD database, including 71,411 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 (71411 hom., cov: 21)
• Consequence: NR3C1 NM_000176.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.149
• Publications: 1 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=-0.77).
• 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.-14+205A>C		intron	N/A	NP_000167.1
	NR3C1	NM_001364185.1		c.-418A>C		5_prime_UTR	Exon 1 of 9	NP_001351114.1
	NR3C1	NM_001364182.1		c.-418A>C		5_prime_UTR	Exon 1 of 9	NP_001351111.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR3C1	ENST00000394464.7	TSL:1 MANE Select	c.-14+205A>C		intron	N/A	ENSP00000377977.2
	NR3C1	ENST00000231509.7	TSL:1	c.-14+205A>C		intron	N/A	ENSP00000231509.3
	NR3C1	ENST00000504572.5	TSL:1	c.-13-2154A>C		intron	N/A	ENSP00000422518.1

Frequencies

GnomAD3 genomes AF: 0.981 AC: 145294 AN: 148038 Hom.: 71362 Cov.: 21

Gnomad AFR AF: 0.934

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.994

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.991

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.986

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

GnomAD4 genome AF: 0.981 AC: 145397 AN: 148144 Hom.: 71411 Cov.: 21 AF XY: 0.982 AC XY: 70879 AN XY: 72178

African (AFR) AF: 0.934 AC: 37105 AN: 39720

American (AMR) AF: 0.994 AC: 14863 AN: 14946

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3462 AN: 3462

East Asian (EAS) AF: 1.00 AC: 4868 AN: 4868

South Asian (SAS) AF: 1.00 AC: 4695 AN: 4696

European-Finnish (FIN) AF: 1.00 AC: 9956 AN: 9956

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

European-Non Finnish (NFE) AF: 1.00 AC: 67255 AN: 67272

Other (OTH) AF: 0.986 AC: 2014 AN: 2042

Alfa AF: 0.991 Hom.: 7433

Bravo AF: 0.979

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	9.3
DANN	Benign	0.63
PhyloP100		0.15
PromoterAI		0.12	Neutral
Mutation Taster		=100/0	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: rs4406157; hg19: chr5-142782571;