rs72542742

Variant names:

• chr5-143400155-C-T
• rs72542742
• NM_000176.3:c.685G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000176.3(NR3C1):​c.685G>A​(p.Ala229Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00139 in 1,614,116 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A229G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (2 hom.)
• Consequence: NR3C1 NM_000176.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 2.28
• 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0075156987).
• BP6: Variant 5-143400155-C-T is Benign according to our data. Variant chr5-143400155-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 713699.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00129 (196/152290) while in subpopulation AMR AF = 0.00275 (42/15298). AF 95% confidence interval is 0.00209. There are 0 homozygotes in GnomAd4. There are 102 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 196 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR3C1	NM_000176.3	MANE Select	c.685G>A	p.Ala229Thr	missense	Exon 2 of 9	NP_000167.1	P04150-1
	NR3C1	NM_001024094.2		c.685G>A	p.Ala229Thr	missense	Exon 2 of 9	NP_001019265.1	E5KQF6
	NR3C1	NM_001364183.2		c.685G>A	p.Ala229Thr	missense	Exon 3 of 10	NP_001351112.1	P04150-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR3C1	ENST00000394464.7	TSL:1 MANE Select	c.685G>A	p.Ala229Thr	missense	Exon 2 of 9	ENSP00000377977.2	P04150-1
	NR3C1	ENST00000231509.7	TSL:1	c.685G>A	p.Ala229Thr	missense	Exon 2 of 9	ENSP00000231509.3	P04150-3
	NR3C1	ENST00000504572.5	TSL:1	c.685G>A	p.Ala229Thr	missense	Exon 3 of 10	ENSP00000422518.1	P04150-3

Frequencies

GnomAD3 genomes AF: 0.00129 AC: 196 AN: 152172 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000458

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00275

Gnomad ASJ AF: 0.00980

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00140

Gnomad OTH AF: 0.00240

GnomAD2 exomes AF: 0.00141 AC: 354 AN: 250844 AF XY: 0.00146

Gnomad AFR exome AF: 0.000126

Gnomad AMR exome AF: 0.000926

Gnomad ASJ exome AF: 0.0124

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00160

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00140 AC: 2053 AN: 1461826 Hom.: 2 Cov.: 32 AF XY: 0.00137 AC XY: 995 AN XY: 727220

African (AFR) AF: 0.000209 AC: 7 AN: 33458

American (AMR) AF: 0.00107 AC: 48 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.0122 AC: 319 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.0000749 AC: 4 AN: 53416

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

European-Non Finnish (NFE) AF: 0.00141 AC: 1563 AN: 1111992

Other (OTH) AF: 0.00182 AC: 110 AN: 60396

GnomAD4 genome AF: 0.00129 AC: 196 AN: 152290 Hom.: 0 Cov.: 32 AF XY: 0.00137 AC XY: 102 AN XY: 74472

African (AFR) AF: 0.000457 AC: 19 AN: 41564

American (AMR) AF: 0.00275 AC: 42 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00980 AC: 34 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10618

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

European-Non Finnish (NFE) AF: 0.00140 AC: 95 AN: 68014

Other (OTH) AF: 0.00237 AC: 5 AN: 2108

Alfa AF: 0.00182 Hom.: 0

Bravo AF: 0.00140

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00244 AC: 21

ExAC AF: 0.00136 AC: 165

EpiCase AF: 0.00174

EpiControl AF: 0.00119

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	17
DANN	Uncertain	1.0
DEOGEN2	Benign	0.18	T
Eigen	Benign	0.060
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.0090	T
MetaRNN	Benign	0.0075	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		2.3
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.47	N
REVEL	Benign	0.063
Sift	Uncertain	0.0050	D
Sift4G	Benign	0.14	T
Polyphen		0.51	P
Vest4		0.068
MVP		0.66
MPC		0.054
ClinPred		0.025	T
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.11
gMVP		0.22
Mutation Taster		=99/1	polymorphism

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: rs72542742; hg19: chr5-142779720; COSMIC: COSV107224060;