4-148078873-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000901.5(NR3C2):c.*2471G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.677 in 152,572 control chromosomes in the GnomAD database, including 35,183 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.68 (35101 hom., cov: 34)
  • Exomes 𝑓: 0.63 (82 hom.)
• Consequence: NR3C2 NM_000901.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.568

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 4-148078873-C-T is Benign according to our data. Variant chr4-148078873-C-T is described in ClinVar as [Benign]. Clinvar id is 347673.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.807 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NR3C2	NM_000901.5	c.*2471G>A		3_prime_UTR_variant	9/9	ENST00000358102.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NR3C2	ENST00000358102.8	c.*2471G>A		3_prime_UTR_variant	9/9	1	NM_000901.5	P4
NR3C2	ENST00000344721.8	c.*2471G>A		3_prime_UTR_variant	9/9	5		P4
NR3C2	ENST00000625323.2	c.*2471G>A		3_prime_UTR_variant	9/9	5		A1

Frequencies

GnomAD3 genomes AF: 0.677 AC: 102962 AN: 152022 Hom.: 35056 Cov.: 34

Gnomad AFR AF: 0.609

Gnomad AMI AF: 0.673

Gnomad AMR AF: 0.760

Gnomad ASJ AF: 0.695

Gnomad EAS AF: 0.827

Gnomad SAS AF: 0.762

Gnomad FIN AF: 0.625

Gnomad MID AF: 0.560

Gnomad NFE AF: 0.690

Gnomad OTH AF: 0.682

GnomAD4 exome AF: 0.632 AC: 273 AN: 432 Hom.: 82 Cov.: 0 AF XY: 0.662 AC XY: 172 AN XY: 260

Gnomad4 FIN exome AF: 0.631

Gnomad4 NFE exome AF: 0.500

Gnomad4 OTH exome AF: 0.750

GnomAD4 genome AF: 0.677 AC: 103065 AN: 152140 Hom.: 35101 Cov.: 34 AF XY: 0.678 AC XY: 50403 AN XY: 74368

Gnomad4 AFR AF: 0.610

Gnomad4 AMR AF: 0.761

Gnomad4 ASJ AF: 0.695

Gnomad4 EAS AF: 0.827

Gnomad4 SAS AF: 0.762

Gnomad4 FIN AF: 0.625

Gnomad4 NFE AF: 0.690

Gnomad4 OTH AF: 0.687

Alfa AF: 0.696 Hom.: 61574

Bravo AF: 0.683

Asia WGS AF: 0.792 AC: 2749 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal dominant pseudohypoaldosteronism type 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
Cadd	Benign	9.7
Dann	Benign	0.76

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: rs2871; hg19: chr4-149000024;