chr1-11858222-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_002521.3(NPPB):​c.380G>A​(p.Gly127Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00000275 in 1,456,628 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

NPPB
NM_002521.3 missense

Scores

5
11
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.06
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.952

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NPPBNM_002521.3 linkc.380G>A p.Gly127Asp 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
NPPBENST00000376468.4 linkc.380G>A p.Gly127Asp missense_variant Exon 2 of 3 1 NM_002521.3 ENSP00000365651.3 P16860

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000811
AC:
2
AN:
246606
Hom.:
0
AF XY:
0.00000750
AC XY:
1
AN XY:
133404
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000296
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000899
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000275
AC:
4
AN:
1456628
Hom.:
0
Cov.:
32
AF XY:
0.00000138
AC XY:
1
AN XY:
724410
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000227
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000270
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
Bravo
AF:
0.0000151
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Mar 01, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.380G>A (p.G127D) alteration is located in exon 2 (coding exon 2) of the NPPB gene. This alteration results from a G to A substitution at nucleotide position 380, causing the glycine (G) at amino acid position 127 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.75
BayesDel_addAF
Uncertain
0.13
D
BayesDel_noAF
Uncertain
0.030
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.74
D
Eigen
Uncertain
0.66
Eigen_PC
Uncertain
0.51
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Benign
0.55
T
M_CAP
Benign
0.035
D
MetaRNN
Pathogenic
0.95
D
MetaSVM
Uncertain
0.38
D
MutationAssessor
Uncertain
2.8
M
PrimateAI
Uncertain
0.52
T
PROVEAN
Pathogenic
-6.5
D
REVEL
Pathogenic
0.68
Sift
Uncertain
0.010
D
Sift4G
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.85
MutPred
0.77
Loss of glycosylation at K129 (P = 0.0927);
MVP
0.88
MPC
0.87
ClinPred
0.95
D
GERP RS
4.5
Varity_R
0.72
gMVP
0.54

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.

Other links and lift over

dbSNP: rs762932355; hg19: chr1-11918279; API