chr1-11858228-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_002521.3(NPPB):​c.374G>T​(p.Gly125Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000304 in 1,610,074 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

NPPB
NM_002521.3 missense

Scores

1
6
12

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.75
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 Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.24711984).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NPPBNM_002521.3 linkc.374G>T p.Gly125Val 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.374G>T p.Gly125Val missense_variant Exon 2 of 3 1 NM_002521.3 ENSP00000365651.3 P16860

Frequencies

GnomAD3 genomes
AF:
0.000164
AC:
25
AN:
152158
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.000579
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000566
AC:
14
AN:
247548
Hom.:
0
AF XY:
0.0000373
AC XY:
5
AN XY:
133958
show subpopulations
Gnomad AFR exome
AF:
0.000804
Gnomad AMR exome
AF:
0.0000295
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:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000165
AC:
24
AN:
1457798
Hom.:
0
Cov.:
32
AF XY:
0.0000124
AC XY:
9
AN XY:
725064
show subpopulations
Gnomad4 AFR exome
AF:
0.000659
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:
0.00
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.000164
AC:
25
AN:
152276
Hom.:
0
Cov.:
32
AF XY:
0.000161
AC XY:
12
AN XY:
74448
show subpopulations
Gnomad4 AFR
AF:
0.000578
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000129
Hom.:
0
Bravo
AF:
0.000136
ESP6500AA
AF:
0.000681
AC:
3
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000741
AC:
9

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Feb 14, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.374G>T (p.G125V) alteration is located in exon 2 (coding exon 2) of the NPPB gene. This alteration results from a G to T substitution at nucleotide position 374, causing the glycine (G) at amino acid position 125 to be replaced by a valine (V). 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
Uncertain
0.43
BayesDel_addAF
Benign
-0.37
T
BayesDel_noAF
Benign
-0.39
CADD
Benign
23
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.70
D
Eigen
Uncertain
0.19
Eigen_PC
Benign
-0.030
FATHMM_MKL
Benign
0.74
D
LIST_S2
Benign
0.58
T
M_CAP
Benign
0.026
D
MetaRNN
Benign
0.25
T
MetaSVM
Benign
-0.80
T
MutationAssessor
Uncertain
2.7
M
PrimateAI
Benign
0.30
T
PROVEAN
Pathogenic
-7.0
D
REVEL
Benign
0.17
Sift
Benign
0.044
D
Sift4G
Uncertain
0.0080
D
Polyphen
0.99
D
Vest4
0.49
MVP
0.58
MPC
0.84
ClinPred
0.37
T
GERP RS
2.5
Varity_R
0.31
gMVP
0.23

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: rs142387227; hg19: chr1-11918285; API