Genetic Variant NPPB:p.Arg72His (chr1-11858387-C-T) – ACMG Classification: Benign (-16 pts)

Variant summary

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

The NM_002521.3(NPPB):c.215G>A(p.Arg72His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00171 in 1,598,676 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0028 ( 4 hom., cov: 32)

Exomes 𝑓: 0.0016 ( 35 hom. )

Consequence

NPPB
NM_002521.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -1.39

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=0.0033937693).

BP6

Variant 1-11858387-C-T is Benign according to our data. Variant chr1-11858387-C-T is described in ClinVar as [Benign]. Clinvar id is 722224.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPPB	NM_002521.3 link	c.215G>A	p.Arg72His	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.215G>A	p.Arg72His	missense_variant	Exon 2 of 3	1	NM_002521.3	ENSP00000365651.3		P16860

Frequencies

GnomAD3 genomes

AF:

0.00277

AC:

421

AN:

152148

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00713

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0311

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000706

Gnomad OTH

AF:

0.000955

GnomAD3 exomes

AF:

0.00364

AC:

862

AN:

236984

Hom.:

AF XY:

0.00358

AC XY:

458

AN XY:

128106

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000125

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00721

Gnomad SAS exome

AF:

0.000179

Gnomad FIN exome

AF:

0.0300

Gnomad NFE exome

AF:

0.000640

Gnomad OTH exome

AF:

0.00451

GnomAD4 exome

AF:

0.00160

AC:

2313

AN:

1446410

Hom.:

Cov.:

AF XY:

0.00155

AC XY:

1109

AN XY:

717710

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000934

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00948

Gnomad4 SAS exome

AF:

0.000202

Gnomad4 FIN exome

AF:

0.0315

Gnomad4 NFE exome

AF:

0.000159

Gnomad4 OTH exome

AF:

0.00116

GnomAD4 genome

AF:

0.00276

AC:

421

AN:

152266

Hom.:

Cov.:

AF XY:

0.00379

AC XY:

282

AN XY:

74444

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00714

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0311

Gnomad4 NFE

AF:

0.000706

Gnomad4 OTH

AF:

0.000945

Alfa

AF:

0.000673

Hom.:

Bravo

AF:

0.000510

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.00315

AC:

383

Asia WGS

AF:

0.00260

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 27, 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

0.056

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.73

CADD

Benign

0.65

DANN

Benign

0.50

DEOGEN2

Benign

0.051

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.012

LIST_S2

Benign

0.37

MetaRNN

Benign

0.0034

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.0

PrimateAI

Benign

0.19

PROVEAN

Benign

0.45

REVEL

Benign

0.0080

Sift

Benign

0.18

Sift4G

Benign

0.14

Polyphen

0.0

Vest4

0.049

MVP

0.18

MPC

0.24

ClinPred

0.018

GERP RS

-2.8

Varity_R

0.020

gMVP

0.12

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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