rs367805474

Variant names:

• chr1-11857662-C-A
• rs367805474
• NM_002521.3:c.398G>T

Your query was ambiguous. Multiple possible variants found:

• chr1-11857662-C-A
• chr1-11857662-C-T

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.398G>T​(p.Arg133Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,744 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R133Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NPPB NM_002521.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.657
• Publications: 0 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=0.093426436).

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.398G>T	p.Arg133Leu	missense	Exon 3 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.398G>T	p.Arg133Leu	missense	Exon 3 of 3	ENSP00000365651.3	P16860
	NPPB	ENST00000945855.1		c.395G>T	p.Arg132Leu	missense	Exon 3 of 3	ENSP00000615914.1
	NPPB	ENST00000945854.1		c.392G>T	p.Arg131Leu	missense	Exon 3 of 3	ENSP00000615913.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461744 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727164

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86224

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111942

Other (OTH) AF: 0.0000331 AC: 2 AN: 60386

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	13
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.46	T
Eigen	Benign	-0.97
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.040	N
LIST_S2	Benign	0.50	T
M_CAP	Benign	0.0095	T
MetaRNN	Benign	0.093	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		-0.66
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-4.0	D
REVEL	Benign	0.042
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.0080	D
Polyphen		0.14	B
Vest4		0.14
MutPred		0.24		Loss of MoRF binding (P = 0.0866)
MVP		0.36
MPC		0.79
ClinPred		0.96	D
GERP RS		-4.2
Varity_R		0.087
gMVP		0.18
Mutation Taster		=95/5	polymorphism

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

Other links and lift over

dbSNP: rs367805474; hg19: chr1-11917719;