rs5530

Variant names:

• chr4-148081258-A-G
• rs5530
• NM_000901.5:c.*86T>C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000901.5(NR3C2):​c.*86T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0199 in 1,524,258 control chromosomes in the GnomAD database, including 387 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (24 hom., cov: 32)
  • Exomes 𝑓: 0.021 (363 hom.)
• Consequence: NR3C2 NM_000901.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.952

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 4-148081258-A-G is Benign according to our data. Variant chr4-148081258-A-G is described in ClinVar as [Benign]. Clinvar id is 347716.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0129 (1960/152334) while in subpopulation NFE AF= 0.0221 (1505/68030). AF 95% confidence interval is 0.0212. There are 24 homozygotes in gnomad4. There are 875 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1960 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR3C2	NM_000901.5	c.*86T>C		3_prime_UTR_variant	Exon 9 of 9	ENST00000358102.8	NP_000892.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NR3C2	ENST00000358102	c.*86T>C		3_prime_UTR_variant	Exon 9 of 9	1	NM_000901.5	ENSP00000350815.3

Frequencies

GnomAD3 genomes AF: 0.0129 AC: 1960 AN: 152216 Hom.: 24 Cov.: 32

Gnomad AFR AF: 0.00470

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00890

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00538

Gnomad FIN AF: 0.00641

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0221

Gnomad OTH AF: 0.00955

GnomAD4 exome AF: 0.0206 AC: 28299 AN: 1371924 Hom.: 363 Cov.: 21 AF XY: 0.0200 AC XY: 13757 AN XY: 686486

Gnomad4 AFR exome AF: 0.00379

Gnomad4 AMR exome AF: 0.00754

Gnomad4 ASJ exome AF: 0.00224

Gnomad4 EAS exome AF: 0.0000255

Gnomad4 SAS exome AF: 0.00612

Gnomad4 FIN exome AF: 0.00774

Gnomad4 NFE exome AF: 0.0250

Gnomad4 OTH exome AF: 0.0186

GnomAD4 genome AF: 0.0129 AC: 1960 AN: 152334 Hom.: 24 Cov.: 32 AF XY: 0.0117 AC XY: 875 AN XY: 74490

Gnomad4 AFR AF: 0.00469

Gnomad4 AMR AF: 0.00889

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00538

Gnomad4 FIN AF: 0.00641

Gnomad4 NFE AF: 0.0221

Gnomad4 OTH AF: 0.00945

Alfa AF: 0.0190 Hom.: 9

Bravo AF: 0.0124

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal dominant pseudohypoaldosteronism type 1 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	6.3
DANN	Benign	0.75

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

Publications

LitVar

Other links and lift over

dbSNP: rs5530; hg19: chr4-149002409;