NM_000901.5:c.1897+15779G>A

Variant names:

• chr4-148244199-C-T
• rs3846317
• NM_000901.5:c.1897+15779G>A

Variant summary

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

The NM_000901.5(NR3C2):​c.1897+15779G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.392 in 151,948 control chromosomes in the GnomAD database, including 11,874 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 0.39 (11874 hom., cov: 32)
• Consequence: NR3C2 NM_000901.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.327
• 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: 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=-0.96).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.479 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR3C2	NM_000901.5	c.1897+15779G>A		intron_variant	Intron 3 of 8	ENST00000358102.8	NP_000892.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NR3C2	ENST00000358102.8	c.1897+15779G>A		intron_variant	Intron 3 of 8	1	NM_000901.5	ENSP00000350815.3

Frequencies

GnomAD3 genomes AF: 0.392 AC: 59552 AN: 151830 Hom.: 11848 Cov.: 32

Gnomad AFR AF: 0.398

Gnomad AMI AF: 0.473

Gnomad AMR AF: 0.487

Gnomad ASJ AF: 0.359

Gnomad EAS AF: 0.379

Gnomad SAS AF: 0.386

Gnomad FIN AF: 0.412

Gnomad MID AF: 0.325

Gnomad NFE AF: 0.366

Gnomad OTH AF: 0.401

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

GnomAD4 genome AF: 0.392 AC: 59628 AN: 151948 Hom.: 11874 Cov.: 32 AF XY: 0.397 AC XY: 29496 AN XY: 74258

African (AFR) AF: 0.399 AC: 16501 AN: 41406

American (AMR) AF: 0.488 AC: 7450 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.359 AC: 1247 AN: 3472

East Asian (EAS) AF: 0.379 AC: 1956 AN: 5166

South Asian (SAS) AF: 0.386 AC: 1856 AN: 4812

European-Finnish (FIN) AF: 0.412 AC: 4342 AN: 10550

Middle Eastern (MID) AF: 0.336 AC: 98 AN: 292

European-Non Finnish (NFE) AF: 0.366 AC: 24905 AN: 67960

Other (OTH) AF: 0.400 AC: 843 AN: 2110

Alfa AF: 0.373 Hom.: 35867

Bravo AF: 0.396

Asia WGS AF: 0.402 AC: 1397 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	1.5
DANN	Benign	0.75
PhyloP100		-0.33
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: rs3846317; hg19: chr4-149165351;