4-148158346-G-T

Variant names:

• chr4-148158346-G-T
• rs3931397
• NM_000901.5:c.2015-3445C>A

Variant summary

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

The NM_000901.5(NR3C2):​c.2015-3445C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.106 in 152,176 control chromosomes in the GnomAD database, including 976 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 0.11 (976 hom., cov: 32)
• Consequence: NR3C2 NM_000901.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.930
• Publications: 16 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)

ENSG00000250354 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.156 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NR3C2	NM_000901.5	c.2015-3445C>A		intron_variant	Intron 4 of 8	ENST00000358102.8	NP_000892.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NR3C2	ENST00000358102.8	c.2015-3445C>A		intron_variant	Intron 4 of 8	1	NM_000901.5	ENSP00000350815.3

Frequencies

GnomAD3 genomes AF: 0.106 AC: 16073 AN: 152058 Hom.: 974 Cov.: 32

Gnomad AFR AF: 0.146

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.0738

Gnomad ASJ AF: 0.177

Gnomad EAS AF: 0.0819

Gnomad SAS AF: 0.165

Gnomad FIN AF: 0.159

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0756

Gnomad OTH AF: 0.0928

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

GnomAD4 genome AF: 0.106 AC: 16078 AN: 152176 Hom.: 976 Cov.: 32 AF XY: 0.108 AC XY: 8036 AN XY: 74406

African (AFR) AF: 0.146 AC: 6064 AN: 41524

American (AMR) AF: 0.0737 AC: 1127 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.177 AC: 614 AN: 3472

East Asian (EAS) AF: 0.0817 AC: 423 AN: 5178

South Asian (SAS) AF: 0.165 AC: 798 AN: 4824

European-Finnish (FIN) AF: 0.159 AC: 1681 AN: 10584

Middle Eastern (MID) AF: 0.0952 AC: 28 AN: 294

European-Non Finnish (NFE) AF: 0.0756 AC: 5138 AN: 67994

Other (OTH) AF: 0.0914 AC: 193 AN: 2112

Alfa AF: 0.0842 Hom.: 1310

Bravo AF: 0.0991

Asia WGS AF: 0.111 AC: 386 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	3.8
DANN	Benign	0.37
PhyloP100		0.93
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: rs3931397; hg19: chr4-149079497;