rs3910044

Variant names:

• chr4-148226671-T-C
• rs3910044
• NM_000901.5:c.1898-31809A>G

Variant summary

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

The NM_000901.5(NR3C2):​c.1898-31809A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.562 in 151,948 control chromosomes in the GnomAD database, including 24,292 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 0.56 (24292 hom., cov: 31)
• Consequence: NR3C2 NM_000901.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.204
• Publications: 10 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=-0.95).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.601 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR3C2	NM_000901.5	MANE Select	c.1898-31809A>G		intron	N/A	NP_000892.2
	NR3C2	NM_001437657.1		c.1910-31809A>G		intron	N/A	NP_001424586.1
	NR3C2	NM_001437654.1		c.1898-31809A>G		intron	N/A	NP_001424583.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR3C2	ENST00000358102.8	TSL:1 MANE Select	c.1898-31809A>G		intron	N/A	ENSP00000350815.3
	NR3C2	ENST00000512865.5	TSL:1	c.1898-31809A>G		intron	N/A	ENSP00000423510.1
	NR3C2	ENST00000511528.1	TSL:5	c.1910-31809A>G		intron	N/A	ENSP00000421481.1

Frequencies

GnomAD3 genomes AF: 0.562 AC: 85384 AN: 151832 Hom.: 24263 Cov.: 31

Gnomad AFR AF: 0.519

Gnomad AMI AF: 0.427

Gnomad AMR AF: 0.530

Gnomad ASJ AF: 0.683

Gnomad EAS AF: 0.485

Gnomad SAS AF: 0.473

Gnomad FIN AF: 0.542

Gnomad MID AF: 0.642

Gnomad NFE AF: 0.606

Gnomad OTH AF: 0.585

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

GnomAD4 genome AF: 0.562 AC: 85460 AN: 151948 Hom.: 24292 Cov.: 31 AF XY: 0.558 AC XY: 41405 AN XY: 74254

African (AFR) AF: 0.520 AC: 21519 AN: 41402

American (AMR) AF: 0.530 AC: 8093 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.683 AC: 2368 AN: 3466

East Asian (EAS) AF: 0.484 AC: 2496 AN: 5156

South Asian (SAS) AF: 0.474 AC: 2284 AN: 4822

European-Finnish (FIN) AF: 0.542 AC: 5734 AN: 10578

Middle Eastern (MID) AF: 0.643 AC: 189 AN: 294

European-Non Finnish (NFE) AF: 0.606 AC: 41148 AN: 67948

Other (OTH) AF: 0.588 AC: 1241 AN: 2110

Alfa AF: 0.597 Hom.: 48423

Bravo AF: 0.565

Asia WGS AF: 0.462 AC: 1604 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.91
DANN	Benign	0.59
PhyloP100		-0.20
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: rs3910044; hg19: chr4-149147823;