chr4-148390576-A-C

Variant names:

• chr4-148390576-A-C
• rs11725509
• NM_000901.5:c.1757+44528T>G

Variant summary

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

The NM_001437657.1(NR3C2):​c.1757+44528T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0601 in 152,206 control chromosomes in the GnomAD database, including 397 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 0.060 (397 hom., cov: 32)
• Consequence: NR3C2 NM_001437657.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.852
• Publications: 5 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=-0.81).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.125 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001437657.1. 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.1757+44528T>G		intron	N/A	NP_000892.2
	NR3C2	NM_001437657.1		c.1757+44528T>G		intron	N/A	NP_001424586.1
	NR3C2	NM_001437654.1		c.1757+44528T>G		intron	N/A	NP_001424583.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR3C2	ENST00000358102.8	TSL:1 MANE Select	c.1757+44528T>G		intron	N/A	ENSP00000350815.3
	NR3C2	ENST00000512865.5	TSL:1	c.1757+44528T>G		intron	N/A	ENSP00000423510.1
	NR3C2	ENST00000511528.1	TSL:5	c.1757+44528T>G		intron	N/A	ENSP00000421481.1

Frequencies

GnomAD3 genomes AF: 0.0601 AC: 9138 AN: 152088 Hom.: 396 Cov.: 32

Gnomad AFR AF: 0.128

Gnomad AMI AF: 0.0516

Gnomad AMR AF: 0.0406

Gnomad ASJ AF: 0.0553

Gnomad EAS AF: 0.000576

Gnomad SAS AF: 0.0355

Gnomad FIN AF: 0.00942

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0375

Gnomad OTH AF: 0.0598

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

GnomAD4 genome AF: 0.0601 AC: 9150 AN: 152206 Hom.: 397 Cov.: 32 AF XY: 0.0573 AC XY: 4262 AN XY: 74420

African (AFR) AF: 0.128 AC: 5325 AN: 41490

American (AMR) AF: 0.0406 AC: 621 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0553 AC: 192 AN: 3470

East Asian (EAS) AF: 0.000578 AC: 3 AN: 5192

South Asian (SAS) AF: 0.0357 AC: 172 AN: 4816

European-Finnish (FIN) AF: 0.00942 AC: 100 AN: 10614

Middle Eastern (MID) AF: 0.0612 AC: 18 AN: 294

European-Non Finnish (NFE) AF: 0.0375 AC: 2548 AN: 68010

Other (OTH) AF: 0.0587 AC: 124 AN: 2112

Alfa AF: 0.0483 Hom.: 700

Bravo AF: 0.0665

Asia WGS AF: 0.0230 AC: 80 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	10
DANN	Benign	0.64
PhyloP100		0.85
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: rs11725509; hg19: chr4-149311728;