1-11858322-C-A

Variant names:

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_002521.3(NPPB):c.280G>T(p.Val94Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00289 in 1,613,860 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0032 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0029 ( 13 hom. )

Consequence

NPPB
NM_002521.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -4.28

Variant links:

Genes affected

NPPB (HGNC:7940): (natriuretic peptide B) This gene is a member of the natriuretic peptide family and encodes a secreted protein which functions as a cardiac hormone. The protein undergoes two cleavage events, one within the cell and a second after secretion into the blood. The protein's biological actions include natriuresis, diuresis, vasorelaxation, inhibition of renin and aldosterone secretion, and a key role in cardiovascular homeostasis. A high concentration of this protein in the bloodstream is indicative of heart failure. The presence of myocardial injury is a significant predictor of mortality in hospitalized coronavirus disease 2019 (COVID-19) patients, and there is evidence of increased levels of natriuretic peptide B in hospitalized non-survivor COVID-19 patients. The protein also acts as an antimicrobial peptide with antibacterial and antifungal activity. Mutations in this gene have been associated with postmenopausal osteoporosis. [provided by RefSeq, Aug 2020]

NPPB links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0061655045).

BP6

Variant 1-11858322-C-A is Benign according to our data. Variant chr1-11858322-C-A is described in ClinVar as [Benign]. Clinvar id is 787694.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-11858322-C-A is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPPB	NM_002521.3 link	c.280G>T	p.Val94Phe	missense_variant	Exon 2 of 3	ENST00000376468.4	NP_002512.1	P16860

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPPB	ENST00000376468.4 link	c.280G>T	p.Val94Phe	missense_variant	Exon 2 of 3	1	NM_002521.3	ENSP00000365651.3		P16860

Frequencies

GnomAD3 genomes

AF:

0.00321

AC:

489

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000700

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00327

Gnomad ASJ

AF:

0.00835

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.0158

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00291

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00335

AC:

839

AN:

250716

Hom.:

AF XY:

0.00356

AC XY:

482

AN XY:

135500

show subpopulations

Gnomad AFR exome

AF:

0.000616

Gnomad AMR exome

AF:

0.00203

Gnomad ASJ exome

AF:

0.00708

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00147

Gnomad FIN exome

AF:

0.0146

Gnomad NFE exome

AF:

0.00273

Gnomad OTH exome

AF:

0.00295

GnomAD4 exome

AF:

0.00286

AC:

4175

AN:

1461544

Hom.:

Cov.:

AF XY:

0.00282

AC XY:

2048

AN XY:

727022

show subpopulations

Gnomad4 AFR exome

AF:

0.000388

Gnomad4 AMR exome

AF:

0.00219

Gnomad4 ASJ exome

AF:

0.00720

Gnomad4 EAS exome

AF:

0.000277

Gnomad4 SAS exome

AF:

0.00159

Gnomad4 FIN exome

AF:

0.0127

Gnomad4 NFE exome

AF:

0.00256

Gnomad4 OTH exome

AF:

0.00306

GnomAD4 genome

AF:

0.00321

AC:

489

AN:

152316

Hom.:

Cov.:

AF XY:

0.00385

AC XY:

287

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.000698

Gnomad4 AMR

AF:

0.00327

Gnomad4 ASJ

AF:

0.00835

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00145

Gnomad4 FIN

AF:

0.0158

Gnomad4 NFE

AF:

0.00291

Gnomad4 OTH

AF:

0.00236

Alfa

AF:

0.00278

Hom.:

Bravo

AF:

0.00239

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00337

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00326

AC:

ExAC

AF:

0.00277

AC:

336

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00256

EpiControl

AF:

0.00273

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 17, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.63

CADD

Benign

0.55

DANN

Uncertain

0.98

DEOGEN2

Benign

0.11

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.026

LIST_S2

Benign

0.34

MetaRNN

Benign

0.0062

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.7

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.92

REVEL

Benign

0.12

Sift

Benign

0.25

Sift4G

Benign

0.38

Polyphen

0.87

Vest4

0.23

MVP

0.17

MPC

0.69

ClinPred

0.011

GERP RS

-7.1

Varity_R

0.058

gMVP

0.13

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over