rs5063

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_006172.4(NPPA):c.94G>A(p.Val32Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.054 in 1,614,070 control chromosomes in the GnomAD database, including 2,754 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.054 ( 278 hom., cov: 32)

Exomes 𝑓: 0.054 ( 2476 hom. )

Consequence

NPPA
NM_006172.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.360

Publications

106 publications found

Variant links:

Genes affected

NPPA (HGNC:7939): (natriuretic peptide A) The protein encoded by this gene belongs to the natriuretic peptide family. Natriuretic peptides are implicated in the control of extracellular fluid volume and electrolyte homeostasis. This protein is synthesized as a large precursor (containing a signal peptide), which is processed to release a peptide from the N-terminus with similarity to vasoactive peptide, cardiodilatin, and another peptide from the C-terminus with natriuretic-diuretic activity. Mutations in this gene have been associated with atrial fibrillation familial type 6. This gene is located adjacent to another member of the natriuretic family of peptides on chromosome 1. [provided by RefSeq, Oct 2015]

NPPA links:

CLCN6 (HGNC:2024): (chloride voltage-gated channel 6) This gene encodes a member of the voltage-dependent chloride channel protein family. Members of this family can function as either chloride channels or antiporters. This protein is primarily localized to late endosomes and functions as a chloride/proton antiporter. Alternate splicing results in both coding and non-coding variants. Additional alternately spliced variants have been described but their full-length structure is unknown. [provided by RefSeq, Mar 2012]

CLCN6 links:

NPPA-AS1 (HGNC:37635): (NPPA antisense RNA 1)

NPPA-AS1 links:

ENSG00000275915 (HGNC:):

ENSG00000275915 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0019845665).

BP6

Variant 1-11847591-C-T is Benign according to our data. Variant chr1-11847591-C-T is described in ClinVar as Benign. ClinVar VariationId is 1169995.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.108 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006172.4. 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
	NPPA	NM_006172.4	MANE Select	c.94G>A	p.Val32Met	missense	Exon 1 of 3	NP_006163.1	P01160
	NPPA-AS1	NR_037806.1		n.1637C>T		non_coding_transcript_exon	Exon 4 of 4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NPPA	ENST00000376480.7	TSL:1 MANE Select	c.94G>A	p.Val32Met	missense	Exon 1 of 3	ENSP00000365663.3	P01160
CLCN6	ENST00000446542.5	TSL:1	n.939C>T		non_coding_transcript_exon	Exon 4 of 4
NPPA	ENST00000953330.1		c.94G>A	p.Val32Met	missense	Exon 1 of 2	ENSP00000623389.1

Frequencies

GnomAD3 genomes

AF:

0.0538

AC:

8183

AN:

152082

Hom.:

278

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0620

Gnomad AMI

AF:

0.0154

Gnomad AMR

AF:

0.0484

Gnomad ASJ

AF:

0.0205

Gnomad EAS

AF:

0.115

Gnomad SAS

AF:

0.115

Gnomad FIN

AF:

0.0290

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.0473

Gnomad OTH

AF:

0.0531

GnomAD2 exomes

AF:

0.0559

AC:

14048

AN:

251492

AF XY:

0.0564

show subpopulations

Gnomad AFR exome

AF:

0.0611

Gnomad AMR exome

AF:

0.0443

Gnomad ASJ exome

AF:

0.0220

Gnomad EAS exome

AF:

0.115

Gnomad FIN exome

AF:

0.0282

Gnomad NFE exome

AF:

0.0457

Gnomad OTH exome

AF:

0.0503

GnomAD4 exome

AF:

0.0540

AC:

78985

AN:

1461870

Hom.:

2476

Cov.:

AF XY:

0.0549

AC XY:

39917

AN XY:

727236

show subpopulations

African (AFR)

AF:

0.0586

AC:

1962

AN:

33478

American (AMR)

AF:

0.0446

AC:

1993

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0218

AC:

571

AN:

26136

East Asian (EAS)

AF:

0.102

AC:

4054

AN:

39700

South Asian (SAS)

AF:

0.0977

AC:

8426

AN:

86258

European-Finnish (FIN)

AF:

0.0305

AC:

1627

AN:

53418

Middle Eastern (MID)

AF:

0.0222

AC:

128

AN:

5768

European-Non Finnish (NFE)

AF:

0.0508

AC:

56478

AN:

1111998

Other (OTH)

AF:

0.0620

AC:

3746

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

5076

10152

15228

20304

25380

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2254

4508

6762

9016

11270

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0538

AC:

8188

AN:

152200

Hom.:

278

Cov.:

AF XY:

0.0533

AC XY:

3967

AN XY:

74398

show subpopulations

African (AFR)

AF:

0.0620

AC:

2575

AN:

41530

American (AMR)

AF:

0.0481

AC:

735

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0205

AC:

AN:

3470

East Asian (EAS)

AF:

0.115

AC:

596

AN:

5168

South Asian (SAS)

AF:

0.115

AC:

553

AN:

4806

European-Finnish (FIN)

AF:

0.0290

AC:

308

AN:

10610

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0473

AC:

3218

AN:

68006

Other (OTH)

AF:

0.0535

AC:

113

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

401

803

1204

1606

2007

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

106

212

318

424

530

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0512

Hom.:

1061

Bravo

AF:

0.0535

TwinsUK

AF:

0.0520

AC:

193

ALSPAC

AF:

0.0532

AC:

205

ESP6500AA

AF:

0.0604

AC:

266

ESP6500EA

AF:

0.0471

AC:

405

ExAC

AF:

0.0562

AC:

6820

Asia WGS

AF:

0.113

AC:

390

AN:

3478

EpiCase

AF:

0.0401

EpiControl

AF:

0.0417

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Atrial fibrillation, familial, 6 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.71

CADD

Benign

2.9

(source)

DANN

Benign

0.82

DEOGEN2

Benign

0.0091

Eigen

Benign

-0.91

Eigen_PC

Benign

-0.99

FATHMM_MKL

Benign

0.034

LIST_S2

Benign

0.72

MetaRNN

Benign

0.0020

MetaSVM

Benign

-1.1

PhyloP100

-0.36

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.27

REVEL

Benign

0.064

Sift

Benign

0.24

Sift4G

Benign

0.26

Vest4

0.091

MPC

0.026

ClinPred

0.0027

GERP RS

-0.38

PromoterAI

-0.0056

Neutral

(source)

gMVP

0.21

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over