NM_000901.5:c.1758-28447C>T

Variant names:

• chr4-148288564-G-A
• rs3846326
• NM_000901.5:c.1758-28447C>T

Variant summary

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

The NM_000901.5(NR3C2):​c.1758-28447C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.719 in 152,184 control chromosomes in the GnomAD database, including 40,197 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 0.72 (40197 hom., cov: 33)
• Consequence: NR3C2 NM_000901.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.16
• Publications: 2 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: Orphanet, ClinGen, Illumina, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• pseudohyperaldosteronism type 2

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.813 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR3C2	NM_000901.5	c.1758-28447C>T		intron_variant	Intron 2 of 8	ENST00000358102.8	NP_000892.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NR3C2	ENST00000358102.8	c.1758-28447C>T		intron_variant	Intron 2 of 8	1	NM_000901.5	ENSP00000350815.3

Frequencies

GnomAD3 genomes AF: 0.720 AC: 109418 AN: 152066 Hom.: 40172 Cov.: 33

Gnomad AFR AF: 0.567

Gnomad AMI AF: 0.909

Gnomad AMR AF: 0.763

Gnomad ASJ AF: 0.811

Gnomad EAS AF: 0.834

Gnomad SAS AF: 0.805

Gnomad FIN AF: 0.705

Gnomad MID AF: 0.851

Gnomad NFE AF: 0.782

Gnomad OTH AF: 0.736

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

GnomAD4 genome AF: 0.719 AC: 109493 AN: 152184 Hom.: 40197 Cov.: 33 AF XY: 0.720 AC XY: 53581 AN XY: 74406

African (AFR) AF: 0.568 AC: 23552 AN: 41500

American (AMR) AF: 0.763 AC: 11668 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.811 AC: 2817 AN: 3472

East Asian (EAS) AF: 0.834 AC: 4313 AN: 5172

South Asian (SAS) AF: 0.806 AC: 3888 AN: 4826

European-Finnish (FIN) AF: 0.705 AC: 7468 AN: 10594

Middle Eastern (MID) AF: 0.847 AC: 249 AN: 294

European-Non Finnish (NFE) AF: 0.781 AC: 53148 AN: 68008

Other (OTH) AF: 0.739 AC: 1561 AN: 2112

Alfa AF: 0.748 Hom.: 11635

Bravo AF: 0.715

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.019
DANN	Benign	0.43
PhyloP100		-2.2
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: rs3846326; hg19: chr4-149209716;