4-148081384-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PM5 BP4

The NM_000901.5(NR3C2):c.2915A>C(p.Glu972Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E972G) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NR3C2 NM_000901.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.91

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 Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr4-148081384-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 8572.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.40378612).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NR3C2	NM_000901.5	c.2915A>C	p.Glu972Ala	missense_variant	9/9	ENST00000358102.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NR3C2	ENST00000358102.8	c.2915A>C	p.Glu972Ala	missense_variant	9/9	1	NM_000901.5	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.10
Cadd	Pathogenic	27
Dann	Uncertain	0.97
DEOGEN2	Uncertain	0.61	D;.;D;.;.
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.95	D
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.40	T;T;T;T;T
MetaSVM	Uncertain	0.62	D
MutationAssessor	Benign	0.69	N;.;N;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-1.9	N;.;N;N;N
REVEL	Pathogenic	0.65
Sift	Benign	0.10	T;.;T;T;T
Sift4G	Benign	0.20	T;T;T;T;T
Vest4		0.51
MutPred		0.42		Loss of solvent accessibility (P = 0.0442);.;Loss of solvent accessibility (P = 0.0442);.;.;
MVP		0.79
MPC		1.3
ClinPred		0.67	D
GERP RS		5.9
Varity_R		0.49
gMVP		0.93

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: rs121912574; hg19: chr4-149002535;