1-11858345-C-T

Variant names:

• chr1-11858345-C-T
• rs1175294119
• NM_002521.3:c.257G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002521.3(NPPB):​c.257G>A​(p.Gly86Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000617 in 1,459,840 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G86A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: NPPB NM_002521.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.372
• Publications: 1 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08383247).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002521.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPPB	NM_002521.3	MANE Select	c.257G>A	p.Gly86Asp	missense	Exon 2 of 3	NP_002512.1	P16860

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPPB	ENST00000376468.4	TSL:1 MANE Select	c.257G>A	p.Gly86Asp	missense	Exon 2 of 3	ENSP00000365651.3	P16860
	NPPB	ENST00000945855.1		c.254G>A	p.Gly85Asp	missense	Exon 2 of 3	ENSP00000615914.1
	NPPB	ENST00000945854.1		c.251G>A	p.Gly84Asp	missense	Exon 2 of 3	ENSP00000615913.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000617 AC: 9 AN: 1459840 Hom.: 0 Cov.: 32 AF XY: 0.00000964 AC XY: 7 AN XY: 725956

African (AFR) AF: 0.00 AC: 0 AN: 33422

American (AMR) AF: 0.00 AC: 0 AN: 44478

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26040

East Asian (EAS) AF: 0.00 AC: 0 AN: 39652

South Asian (SAS) AF: 0.00 AC: 0 AN: 86052

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53376

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000720 AC: 8 AN: 1110790

Other (OTH) AF: 0.0000166 AC: 1 AN: 60264

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.66
CADD	Benign	5.6
DANN	Benign	0.97
DEOGEN2	Benign	0.22	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.43	T
M_CAP	Benign	0.0042	T
MetaRNN	Benign	0.084	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
PhyloP100		-0.37
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.011
Sift	Benign	0.29	T
Sift4G	Benign	0.14	T
Polyphen		0.014	B
Vest4		0.13
MutPred		0.54		Loss of MoRF binding (P = 0.0773)
MVP		0.22
MPC		0.28
ClinPred		0.14	T
GERP RS		-1.3
Varity_R		0.068
gMVP		0.18
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1175294119; hg19: chr1-11918402;