rs5527

Variant names:

• chr4-148435200-T-C
• rs5527
• NM_000901.5:c.1661A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000901.5(NR3C2):​c.1661A>G​(p.Asn554Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00133 in 1,614,142 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N554Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0034 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (22 hom.)
• Consequence: NR3C2 NM_000901.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.02
• Publications: 17 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003315121).
• BP6: Variant 4-148435200-T-C is Benign according to our data. Variant chr4-148435200-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 347730.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00339 (516/152254) while in subpopulation EAS AF = 0.0285 (148/5184). AF 95% confidence interval is 0.0248. There are 5 homozygotes in GnomAd4. There are 269 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 516 AD,Unknown gene.

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.1661A>G	p.Asn554Ser	missense	Exon 2 of 9	NP_000892.2
	NR3C2	NM_001437657.1		c.1661A>G	p.Asn554Ser	missense	Exon 2 of 9	NP_001424586.1
	NR3C2	NM_001437654.1		c.1661A>G	p.Asn554Ser	missense	Exon 2 of 9	NP_001424583.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NR3C2	ENST00000358102.8	TSL:1 MANE Select	c.1661A>G	p.Asn554Ser	missense	Exon 2 of 9	ENSP00000350815.3
	NR3C2	ENST00000512865.5	TSL:1	c.1661A>G	p.Asn554Ser	missense	Exon 2 of 8	ENSP00000423510.1
	NR3C2	ENST00000511528.1	TSL:5	c.1661A>G	p.Asn554Ser	missense	Exon 1 of 8	ENSP00000421481.1

Frequencies

GnomAD3 genomes AF: 0.00340 AC: 518 AN: 152136 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00790

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0285

Gnomad SAS AF: 0.00145

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00297 AC: 748 AN: 251464 AF XY: 0.00272

Gnomad AFR exome AF: 0.00769

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0317

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000879

Gnomad OTH exome AF: 0.000651

GnomAD4 exome AF: 0.00111 AC: 1628 AN: 1461888 Hom.: 22 Cov.: 31 AF XY: 0.00109 AC XY: 791 AN XY: 727248

African (AFR) AF: 0.00795 AC: 266 AN: 33480

American (AMR) AF: 0.000470 AC: 21 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0269 AC: 1068 AN: 39700

South Asian (SAS) AF: 0.000626 AC: 54 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.0000845 AC: 94 AN: 1112006

Other (OTH) AF: 0.00204 AC: 123 AN: 60396

GnomAD4 genome AF: 0.00339 AC: 516 AN: 152254 Hom.: 5 Cov.: 32 AF XY: 0.00361 AC XY: 269 AN XY: 74458

African (AFR) AF: 0.00787 AC: 327 AN: 41538

American (AMR) AF: 0.00144 AC: 22 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.0285 AC: 148 AN: 5184

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68008

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00163 Hom.: 8

Bravo AF: 0.00368

ESP6500AA AF: 0.00635 AC: 28

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00287 AC: 348

Asia WGS AF: 0.0100 AC: 35 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely 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
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	12
DANN	Benign	0.66
DEOGEN2	Benign	0.30	T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.0033	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	-0.69	N
PhyloP100		1.0
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.69	N
REVEL	Benign	0.25
Sift	Benign	0.49	T
Sift4G	Benign	0.64	T
Vest4		0.051
MVP		0.48
MPC		0.11
ClinPred		0.011	T
GERP RS		-2.2
Varity_R		0.047
gMVP		0.10
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs5527; hg19: chr4-149356352; COSMIC: COSV100678726;