NM_000901.5:c.*412C>T

Variant names:

• chr4-148080932-G-A
• rs17024360
• NM_000901.5:c.*412C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_000901.5(NR3C2):​c.*412C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0085 in 317,988 control chromosomes in the GnomAD database, including 68 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (59 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (9 hom.)
• Consequence: NR3C2 NM_000901.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.341
• Publications: 4 publications found

Genes affected

NR3C2 (HGNC:7979): (nuclear receptor subfamily 3 group C member 2) This gene encodes the mineralocorticoid receptor, which mediates aldosterone actions on salt and water balance within restricted target cells. The protein functions as a ligand-dependent transcription factor that binds to mineralocorticoid response elements in order to transactivate target genes. Mutations in this gene cause autosomal dominant pseudohypoaldosteronism type I, a disorder characterized by urinary salt wasting. Defects in this gene are also associated with early onset hypertension with severe exacerbation in pregnancy. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2009]

NR3C2 Gene-Disease associations (from GenCC):

• autosomal dominant pseudohypoaldosteronism type 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet, Illumina, Ambry Genetics
• pseudohyperaldosteronism type 2

  Inheritance: Unknown, AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), ClinGen

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 4-148080932-G-A is Benign according to our data. Variant chr4-148080932-G-A is described in ClinVar as Benign. ClinVar VariationId is 347713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0512 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000901.5. 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
	NR3C2	NM_000901.5	MANE Select	c.*412C>T		3_prime_UTR	Exon 9 of 9	NP_000892.2	B0ZBF6
	NR3C2	NM_001437657.1		c.*412C>T		3_prime_UTR	Exon 9 of 9	NP_001424586.1
	NR3C2	NM_001437654.1		c.*412C>T		3_prime_UTR	Exon 9 of 9	NP_001424583.1	B0ZBF6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR3C2	ENST00000358102.8	TSL:1 MANE Select	c.*412C>T		3_prime_UTR	Exon 9 of 9	ENSP00000350815.3	P08235-1
	NR3C2	ENST00000512865.5	TSL:1	c.*412C>T		3_prime_UTR	Exon 8 of 8	ENSP00000423510.1	P08235-4
	NR3C2	ENST00000625323.2	TSL:5	c.*412C>T		3_prime_UTR	Exon 9 of 9	ENSP00000486719.1	P08235-3

Frequencies

GnomAD3 genomes AF: 0.0154 AC: 2343 AN: 151860 Hom.: 59 Cov.: 32

Gnomad AFR AF: 0.0530

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00610

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.000500

Gnomad OTH AF: 0.0120

GnomAD4 exome AF: 0.00211 AC: 351 AN: 166010 Hom.: 9 Cov.: 0 AF XY: 0.00173 AC XY: 158 AN XY: 91236

African (AFR) AF: 0.0533 AC: 264 AN: 4956

American (AMR) AF: 0.00266 AC: 29 AN: 10916

Ashkenazi Jewish (ASJ) AF: 0.000191 AC: 1 AN: 5244

East Asian (EAS) AF: 0.00 AC: 0 AN: 7488

South Asian (SAS) AF: 0.000248 AC: 8 AN: 32200

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7988

Middle Eastern (MID) AF: 0.00870 AC: 6 AN: 690

European-Non Finnish (NFE) AF: 0.000259 AC: 23 AN: 88636

Other (OTH) AF: 0.00253 AC: 20 AN: 7892

GnomAD4 genome AF: 0.0155 AC: 2351 AN: 151978 Hom.: 59 Cov.: 32 AF XY: 0.0154 AC XY: 1140 AN XY: 74264

African (AFR) AF: 0.0530 AC: 2195 AN: 41408

American (AMR) AF: 0.00609 AC: 93 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10532

Middle Eastern (MID) AF: 0.0103 AC: 3 AN: 292

European-Non Finnish (NFE) AF: 0.000500 AC: 34 AN: 68000

Other (OTH) AF: 0.0118 AC: 25 AN: 2112

Alfa AF: 0.00877 Hom.: 13

Bravo AF: 0.0173

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Autosomal dominant pseudohypoaldosteronism type 1 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	11
DANN	Benign	0.86
PhyloP100		0.34
Mutation Taster		=100/0	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: rs17024360; hg19: chr4-149002083;