1-11858780-A-G

Variant names:

• chr1-11858780-A-G
• rs35628673
• NM_002521.3:c.54T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_002521.3(NPPB):​c.54T>C​(p.His18His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00274 in 1,614,160 control chromosomes in the GnomAD database, including 75 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (34 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (41 hom.)
• Consequence: NPPB NM_002521.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.347
• Publications: 2 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 1-11858780-A-G is Benign according to our data. Variant chr1-11858780-A-G is described in ClinVar as Benign. ClinVar VariationId is 777883.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.347 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0133 (2029/152268) while in subpopulation AFR AF = 0.0449 (1867/41548). AF 95% confidence interval is 0.0432. There are 34 homozygotes in GnomAd4. There are 950 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 34 AR gene

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.54T>C	p.His18His	synonymous	Exon 1 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.54T>C	p.His18His	synonymous	Exon 1 of 3	ENSP00000365651.3	P16860
	NPPB	ENST00000945855.1		c.54T>C	p.His18His	synonymous	Exon 1 of 3	ENSP00000615914.1
	NPPB	ENST00000945854.1		c.54T>C	p.His18His	synonymous	Exon 1 of 3	ENSP00000615913.1

Frequencies

GnomAD3 genomes AF: 0.0133 AC: 2021 AN: 152150 Hom.: 34 Cov.: 32

Gnomad AFR AF: 0.0449

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00556

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000456

Gnomad OTH AF: 0.0110

GnomAD2 exomes AF: 0.00379 AC: 952 AN: 251448 AF XY: 0.00284

Gnomad AFR exome AF: 0.0481

Gnomad AMR exome AF: 0.00188

Gnomad ASJ exome AF: 0.00456

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000360

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00164 AC: 2397 AN: 1461892 Hom.: 41 Cov.: 32 AF XY: 0.00142 AC XY: 1030 AN XY: 727248

African (AFR) AF: 0.0475 AC: 1589 AN: 33480

American (AMR) AF: 0.00226 AC: 101 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00429 AC: 112 AN: 26136

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39700

South Asian (SAS) AF: 0.000151 AC: 13 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00520 AC: 30 AN: 5768

European-Non Finnish (NFE) AF: 0.000239 AC: 266 AN: 1112012

Other (OTH) AF: 0.00465 AC: 281 AN: 60396

GnomAD4 genome AF: 0.0133 AC: 2029 AN: 152268 Hom.: 34 Cov.: 32 AF XY: 0.0128 AC XY: 950 AN XY: 74466

African (AFR) AF: 0.0449 AC: 1867 AN: 41548

American (AMR) AF: 0.00556 AC: 85 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00432 AC: 15 AN: 3470

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000456 AC: 31 AN: 68002

Other (OTH) AF: 0.0123 AC: 26 AN: 2114

Alfa AF: 0.00543 Hom.: 9

Bravo AF: 0.0151

Asia WGS AF: 0.0120 AC: 41 AN: 3478

EpiCase AF: 0.000600

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	3.0
DANN	Benign	0.66
PhyloP100		0.35
PromoterAI		-0.054	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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: rs35628673; hg19: chr1-11918837;