5-32786283-A-G

Position:

• chr5-32786283-A-G

Variant summary

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

The ENST00000265074.13(NPR3):​c.1564A>G​(p.Asn522Asp) variant causes a missense change. The variant allele was found at a frequency of 0.21 in 1,581,236 control chromosomes in the GnomAD database, including 36,640 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. N522N) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.19 (2889 hom., cov: 32)
  • Exomes 𝑓: 0.21 (33751 hom.)
• Consequence: NPR3 ENST00000265074.13 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 4.84

Genes affected

NPR3 (HGNC:7945): (natriuretic peptide receptor 3) This gene encodes one of three natriuretic peptide receptors. Natriutetic peptides are small peptides which regulate blood volume and pressure, pulmonary hypertension, and cardiac function as well as some metabolic and growth processes. The product of this gene encodes a natriuretic peptide receptor responsible for clearing circulating and extracellular natriuretic peptides through endocytosis of the receptor. Multiple transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Feb 2011]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0012596548).
• BP6: Variant 5-32786283-A-G is Benign according to our data. Variant chr5-32786283-A-G is described in ClinVar as [Benign]. Clinvar id is 1240702.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.269 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPR3	NM_001204375.2	c.1564A>G	p.Asn522Asp	missense_variant	8/8	ENST00000265074.13	NP_001191304.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPR3	ENST00000265074.13	c.1564A>G	p.Asn522Asp	missense_variant	8/8	1	NM_001204375.2	ENSP00000265074	P4
NPR3	ENST00000415167.2	c.1561A>G	p.Asn521Asp	missense_variant	8/8	1		ENSP00000398028	A1
NPR3	ENST00000434067.6	c.916A>G	p.Asn306Asp	missense_variant	8/8	5		ENSP00000388408
NPR3	ENST00000326958.5	c.913A>G	p.Asn305Asp	missense_variant	8/8	2		ENSP00000318340

Frequencies

GnomAD3 genomes AF: 0.187 AC: 28373 AN: 152094 Hom.: 2891 Cov.: 32

Gnomad AFR AF: 0.112

Gnomad AMI AF: 0.343

Gnomad AMR AF: 0.225

Gnomad ASJ AF: 0.142

Gnomad EAS AF: 0.204

Gnomad SAS AF: 0.281

Gnomad FIN AF: 0.226

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.210

Gnomad OTH AF: 0.165

GnomAD3 exomes AF: 0.207 AC: 49130 AN: 237278 Hom.: 5394 AF XY: 0.210 AC XY: 26963 AN XY: 128260

Gnomad AFR exome AF: 0.106

Gnomad AMR exome AF: 0.205

Gnomad ASJ exome AF: 0.150

Gnomad EAS exome AF: 0.203

Gnomad SAS exome AF: 0.274

Gnomad FIN exome AF: 0.225

Gnomad NFE exome AF: 0.207

Gnomad OTH exome AF: 0.192

GnomAD4 exome AF: 0.213 AC: 303721 AN: 1429024 Hom.: 33751 Cov.: 25 AF XY: 0.214 AC XY: 152270 AN XY: 711392

Gnomad4 AFR exome AF: 0.106

Gnomad4 AMR exome AF: 0.206

Gnomad4 ASJ exome AF: 0.151

Gnomad4 EAS exome AF: 0.225

Gnomad4 SAS exome AF: 0.269

Gnomad4 FIN exome AF: 0.224

Gnomad4 NFE exome AF: 0.214

Gnomad4 OTH exome AF: 0.198

GnomAD4 genome AF: 0.186 AC: 28380 AN: 152212 Hom.: 2889 Cov.: 32 AF XY: 0.191 AC XY: 14209 AN XY: 74406

Gnomad4 AFR AF: 0.112

Gnomad4 AMR AF: 0.225

Gnomad4 ASJ AF: 0.142

Gnomad4 EAS AF: 0.204

Gnomad4 SAS AF: 0.282

Gnomad4 FIN AF: 0.226

Gnomad4 NFE AF: 0.210

Gnomad4 OTH AF: 0.167

Alfa AF: 0.204 Hom.: 7837

Bravo AF: 0.179

TwinsUK AF: 0.219 AC: 812

ALSPAC AF: 0.225 AC: 866

ESP6500AA AF: 0.117 AC: 428

ESP6500EA AF: 0.202 AC: 1649

ExAC AF: 0.206 AC: 24861

Asia WGS AF: 0.247 AC: 860 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	This variant is associated with the following publications: (PMID: 24465655, 23493048) -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	14
DANN	Uncertain	0.99
DEOGEN2	Benign	0.015	T;.;T;.
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.067
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.62	T;T;T;T
MetaRNN	Benign	0.0013	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	.;.;L;.
MutationTaster	Benign	0.039	P;P;P;P
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.57	N;.;N;N
REVEL	Benign	0.055
Sift	Benign	0.31	T;.;T;T
Sift4G	Benign	0.22	T;T;T;T
Polyphen		0.0010	.;.;B;.
Vest4		0.039
ClinPred		0.015	T
GERP RS		5.0
Varity_R		0.14
gMVP		0.22

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs2270915; hg19: chr5-32786389; COSMIC: COSV54084512; COSMIC: COSV54084512;