rs5534

Positions:

• chr4-148079934-T-C
• chr4-148079934-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000901.5(NR3C2):​c.*1410A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.499 in 152,086 control chromosomes in the GnomAD database, including 21,143 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.50 (21126 hom., cov: 32)
  • Exomes 𝑓: 0.62 (17 hom.)
• Consequence: NR3C2 NM_000901.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.570

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=-0.95).
• BP6: Variant 4-148079934-T-C is Benign according to our data. Variant chr4-148079934-T-C is described in ClinVar as [Benign]. Clinvar id is 347695.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.809 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NR3C2	NM_000901.5	c.*1410A>G		3_prime_UTR_variant	9/9	ENST00000358102.8	NP_000892.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NR3C2	ENST00000358102.8	c.*1410A>G		3_prime_UTR_variant	9/9	1	NM_000901.5	ENSP00000350815	P4
NR3C2	ENST00000344721.8	c.*1410A>G		3_prime_UTR_variant	9/9	5		ENSP00000341390	P4
NR3C2	ENST00000625323.2	c.*1410A>G		3_prime_UTR_variant	9/9	5		ENSP00000486719	A1

Frequencies

GnomAD3 genomes AF: 0.499 AC: 75738 AN: 151874 Hom.: 21114 Cov.: 32

Gnomad AFR AF: 0.237

Gnomad AMI AF: 0.565

Gnomad AMR AF: 0.643

Gnomad ASJ AF: 0.558

Gnomad EAS AF: 0.830

Gnomad SAS AF: 0.651

Gnomad FIN AF: 0.553

Gnomad MID AF: 0.380

Gnomad NFE AF: 0.578

Gnomad OTH AF: 0.500

GnomAD4 exome AF: 0.617 AC: 58 AN: 94 Hom.: 17 Cov.: 0 AF XY: 0.661 AC XY: 41 AN XY: 62

Gnomad4 FIN exome AF: 0.593

Gnomad4 OTH exome AF: 0.833

GnomAD4 genome AF: 0.498 AC: 75761 AN: 151992 Hom.: 21126 Cov.: 32 AF XY: 0.503 AC XY: 37349 AN XY: 74274

Gnomad4 AFR AF: 0.236

Gnomad4 AMR AF: 0.644

Gnomad4 ASJ AF: 0.558

Gnomad4 EAS AF: 0.830

Gnomad4 SAS AF: 0.649

Gnomad4 FIN AF: 0.553

Gnomad4 NFE AF: 0.578

Gnomad4 OTH AF: 0.508

Alfa AF: 0.567 Hom.: 41011

Bravo AF: 0.493

Asia WGS AF: 0.715 AC: 2484 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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

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

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.17
DANN	Benign	0.39

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: rs5534; hg19: chr4-149001085;