rs5063

Positions:

chr1-11847591-C-T

Variant summary

Our verdict is Benign. Variant got -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. 13/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

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

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:):

NPPA-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 1169995.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-11847591-C-T is described in Lovd as [Benign].

BA1

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPPA	NM_006172.4 linkuse as main transcript	c.94G>A	p.Val32Met	missense_variant	1/3	ENST00000376480.7	NP_006163.1
NPPA-AS1	NR_037806.1 linkuse as main transcript	n.1637C>T		non_coding_transcript_exon_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPPA	ENST00000376480.7 linkuse as main transcript	c.94G>A	p.Val32Met	missense_variant	1/3	1	NM_006172.4	ENSP00000365663	P1
	ENST00000617059.1 linkuse as main transcript			downstream_gene_variant

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

GnomAD3 exomes

AF:

0.0559

AC:

14048

AN:

251492

Hom.:

542

AF XY:

0.0564

AC XY:

7671

AN XY:

135920

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 SAS exome

AF:

0.100

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

Gnomad4 AFR exome

AF:

0.0586

Gnomad4 AMR exome

AF:

0.0446

Gnomad4 ASJ exome

AF:

0.0218

Gnomad4 EAS exome

AF:

0.102

Gnomad4 SAS exome

AF:

0.0977

Gnomad4 FIN exome

AF:

0.0305

Gnomad4 NFE exome

AF:

0.0508

Gnomad4 OTH exome

AF:

0.0620

GnomAD4 genome

AF:

0.0538

AC:

8188

AN:

152200

Hom.:

278

Cov.:

AF XY:

0.0533

AC XY:

3967

AN XY:

74398

show subpopulations

Gnomad4 AFR

AF:

0.0620

Gnomad4 AMR

AF:

0.0481

Gnomad4 ASJ

AF:

0.0205

Gnomad4 EAS

AF:

0.115

Gnomad4 SAS

AF:

0.115

Gnomad4 FIN

AF:

0.0290

Gnomad4 NFE

AF:

0.0473

Gnomad4 OTH

AF:

0.0535

Alfa

AF:

0.0492

Hom.:

552

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

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 30, 2019	This variant is associated with the following publications: (PMID: 16368448, 25854761, 17984371, 20543198, 20064500) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Atrial fibrillation, familial, 6

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.71

CADD

Benign

2.9

DANN

Benign

0.82

DEOGEN2

Benign

0.0091

.;T

Eigen

Benign

-0.91

Eigen_PC

Benign

-0.99

FATHMM_MKL

Benign

0.034

LIST_S2

Benign

0.72

.;T

MetaRNN

Benign

0.0020

T;T

MetaSVM

Benign

-1.1

MutationTaster

Benign

1.0

D;N

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.27

N;.

REVEL

Benign

0.064

Sift

Benign

0.24

T;.

Sift4G

Benign

0.26

T;T

Vest4

0.091

MPC

0.026

ClinPred

0.0027

GERP RS

-0.38

gMVP

0.21

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over