Genetic Variant NPR1:p.Pro7Leu (chr1-153679128-C-T) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_000906.4(NPR1):c.20C>T(p.Pro7Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000295 in 1,286,548 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict 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. P7H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000030 ( 0 hom. )

Consequence

NPR1
NM_000906.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.967

Publications

0 publications found

Variant links:

Genes affected

NPR1 (HGNC:7943): (natriuretic peptide receptor 1) Guanylyl cyclases, catalyzing the production of cGMP from GTP, are classified as soluble and membrane forms (Garbers and Lowe, 1994 [PubMed 7982997]). The membrane guanylyl cyclases, often termed guanylyl cyclases A through F, form a family of cell-surface receptors with a similar topographic structure: an extracellular ligand-binding domain, a single membrane-spanning domain, and an intracellular region that contains a protein kinase-like domain and a cyclase catalytic domain. GC-A and GC-B function as receptors for natriuretic peptides; they are also referred to as atrial natriuretic peptide receptor A (NPR1) and type B (NPR2; MIM 108961). Also see NPR3 (MIM 108962), which encodes a protein with only the ligand-binding transmembrane and 37-amino acid cytoplasmic domains. NPR1 is a membrane-bound guanylate cyclase that serves as the receptor for both atrial and brain natriuretic peptides (ANP (MIM 108780) and BNP (MIM 600295), respectively).[supplied by OMIM, May 2009]

NPR1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.15329942).

BS2

High AC in GnomAdExome4 at 38 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPR1	NM_000906.4 link	c.20C>T	p.Pro7Leu	missense_variant	Exon 1 of 22	ENST00000368680.4	NP_000897.3	P16066A0A140VJE6
NPR1	XM_005245218.3 link	c.20C>T	p.Pro7Leu	missense_variant	Exon 1 of 21		XP_005245275.1
NPR1	XM_017001374.3 link	c.20C>T	p.Pro7Leu	missense_variant	Exon 1 of 14		XP_016856863.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPR1	ENST00000368680.4 link	c.20C>T	p.Pro7Leu	missense_variant	Exon 1 of 22	1	NM_000906.4	ENSP00000357669.3		P16066

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.0000295

AC:

AN:

1286548

Hom.:

Cov.:

AF XY:

0.0000254

AC XY:

AN XY:

630526

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25104

American (AMR)

AF:

0.00

AC:

AN:

18978

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19360

East Asian (EAS)

AF:

0.00

AC:

AN:

30092

South Asian (SAS)

AF:

0.00

AC:

AN:

65216

European-Finnish (FIN)

AF:

0.00

AC:

AN:

31628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3828

European-Non Finnish (NFE)

AF:

0.0000366

AC:

AN:

1039054

Other (OTH)

AF:

0.00

AC:

AN:

53288

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.073

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.24

Eigen

Benign

-0.86

Eigen_PC

Benign

-0.76

FATHMM_MKL

Benign

0.063

LIST_S2

Benign

0.62

M_CAP

Pathogenic

0.34

MetaRNN

Benign

0.15

MetaSVM

Benign

-0.91

MutationAssessor

Benign

0.69

PhyloP100

0.97

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-0.67

REVEL

Benign

0.26

Sift

Benign

0.29

Sift4G

Benign

0.81

Polyphen

0.0

Vest4

0.088

MutPred

0.21

Gain of MoRF binding (P = 0.0231);

MVP

0.82

MPC

0.71

ClinPred

0.081

GERP RS

3.6

PromoterAI

0.0018

Neutral

(source)

Varity_R

0.031

gMVP

0.56

Mutation Taster

=97/3

polymorphism

(source)

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

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1-153679128-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over