rs6192

Variant names:

• chr5-143400647-A-C
• rs6192
• NM_000176.3:c.193T>G

Your query was ambiguous. Multiple possible variants found:

• chr5-143400647-A-C
• chr5-143400647-A-G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001204259.2(NR3C1):​c.-63T>G variant causes a 5 prime UTR premature start codon gain change. The variant allele was found at a frequency of 0.000787 in 1,614,040 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0044 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00041 (2 hom.)
• Consequence: NR3C1 NM_001204259.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 4.53
• Publications: 9 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: Orphanet, Laboratory for Molecular Medicine, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008410096).
• BP6: Variant 5-143400647-A-C is Benign according to our data. Variant chr5-143400647-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 722582.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00437 (665/152314) while in subpopulation AFR AF = 0.0152 (633/41568). AF 95% confidence interval is 0.0142. There are 2 homozygotes in GnomAd4. There are 327 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 665 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001204259.2. 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_000176.3	MANE Select	c.193T>G	p.Phe65Val	missense	Exon 2 of 9	NP_000167.1	P04150-1
	NR3C1	NM_001204259.2		c.-63T>G		5_prime_UTR_premature_start_codon_gain	Exon 2 of 9	NP_001191188.1	P04150-11
	NR3C1	NM_001204260.2		c.-75T>G		5_prime_UTR_premature_start_codon_gain	Exon 2 of 9	NP_001191189.1	P04150-12

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR3C1	ENST00000394464.7	TSL:1 MANE Select	c.193T>G	p.Phe65Val	missense	Exon 2 of 9	ENSP00000377977.2	P04150-1
	NR3C1	ENST00000231509.7	TSL:1	c.193T>G	p.Phe65Val	missense	Exon 2 of 9	ENSP00000231509.3	P04150-3
	NR3C1	ENST00000504572.5	TSL:1	c.193T>G	p.Phe65Val	missense	Exon 3 of 10	ENSP00000422518.1	P04150-3

Frequencies

GnomAD3 genomes AF: 0.00434 AC: 660 AN: 152196 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0152

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00336

GnomAD2 exomes AF: 0.000970 AC: 244 AN: 251438 AF XY: 0.000743

Gnomad AFR exome AF: 0.0137

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.000652

GnomAD4 exome AF: 0.000414 AC: 605 AN: 1461726 Hom.: 2 Cov.: 32 AF XY: 0.000367 AC XY: 267 AN XY: 727120

African (AFR) AF: 0.0148 AC: 496 AN: 33480

American (AMR) AF: 0.000581 AC: 26 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00000899 AC: 10 AN: 1111850

Other (OTH) AF: 0.00113 AC: 68 AN: 60394

GnomAD4 genome AF: 0.00437 AC: 665 AN: 152314 Hom.: 2 Cov.: 32 AF XY: 0.00439 AC XY: 327 AN XY: 74486

African (AFR) AF: 0.0152 AC: 633 AN: 41568

American (AMR) AF: 0.00137 AC: 21 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68022

Other (OTH) AF: 0.00332 AC: 7 AN: 2108

Alfa AF: 0.00168 Hom.: 3

Bravo AF: 0.00474

ESP6500AA AF: 0.0143 AC: 63

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00126 AC: 153

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Glucocorticoid resistance (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	19
DANN	Benign	0.94
DEOGEN2	Benign	0.15	T
Eigen	Benign	0.018
Eigen_PC	Benign	0.12
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.85	T
MetaRNN	Benign	0.0084	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L
PhyloP100		4.5
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.010	N
REVEL	Benign	0.081
Sift	Benign	0.33	T
Sift4G	Benign	0.58	T
Polyphen		0.68	P
Vest4		0.61
MVP		0.69
MPC		0.14
ClinPred		0.016	T
GERP RS		4.8
PromoterAI		-0.023	Neutral
Varity_R		0.070
gMVP		0.16
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs6192; hg19: chr5-142780212;