chr1-11858452-C-G

Variant names:

• chr1-11858452-C-G
• rs371722685
• NM_002521.3:c.150G>C

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.150G>C​(p.Leu50Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000719 in 1,390,138 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: NPPB NM_002521.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.952
• 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=0.20265359).

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.150G>C	p.Leu50Phe	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.150G>C	p.Leu50Phe	missense	Exon 2 of 3	ENSP00000365651.3	P16860
	NPPB	ENST00000945855.1		c.147G>C	p.Leu49Phe	missense	Exon 2 of 3	ENSP00000615914.1
	NPPB	ENST00000945854.1		c.144G>C	p.Leu48Phe	missense	Exon 2 of 3	ENSP00000615913.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.19e-7 AC: 1 AN: 1390138 Hom.: 0 Cov.: 32 AF XY: 0.00000146 AC XY: 1 AN XY: 683404

African (AFR) AF: 0.00 AC: 0 AN: 31366

American (AMR) AF: 0.00 AC: 0 AN: 34514

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21338

East Asian (EAS) AF: 0.00 AC: 0 AN: 39016

South Asian (SAS) AF: 0.00 AC: 0 AN: 74586

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50366

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5428

European-Non Finnish (NFE) AF: 9.29e-7 AC: 1 AN: 1076260

Other (OTH) AF: 0.00 AC: 0 AN: 57264

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	7.1
DANN	Benign	0.91
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.80
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.45	T
M_CAP	Benign	0.0049	T
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.9	L
PhyloP100		-0.95
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.11
Sift	Uncertain	0.0080	D
Sift4G	Benign	0.11	T
Polyphen		1.0	D
Vest4		0.22
MutPred		0.50		Gain of methylation at R47 (P = 0.1831)
MVP		0.30
MPC		0.76
ClinPred		0.28	T
GERP RS		-6.8
PromoterAI		0.021	Neutral
Varity_R		0.053
gMVP		0.51
Mutation Taster		=93/7	polymorphism

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

Other links and lift over

dbSNP: rs371722685; hg19: chr1-11918509;