rs5065

Positions:

chr1-11846011-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM4BP6_Very_StrongBA1

The NM_006172.4(NPPA):c.454T>C(p.Ter152ArgextTer2) variant causes a stop lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.153 in 1,613,250 control chromosomes in the GnomAD database, including 22,231 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.21 ( 4472 hom., cov: 32)

Exomes 𝑓: 0.15 ( 17759 hom. )

Consequence

NPPA
NM_006172.4 stop_lost

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.328

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 -14 ACMG points.

PM4

Stoplost variant in NM_006172.4 Downstream stopcodon found after 1 codons.

BP6

Variant 1-11846011-A-G is Benign according to our data. Variant chr1-11846011-A-G is described in ClinVar as [Benign]. Clinvar id is 226855.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-11846011-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.398 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.454T>C	p.Ter152ArgextTer2	stop_lost	3/3	ENST00000376480.7	NP_006163.1
NPPA-AS1	NR_037806.1 linkuse as main transcript	n.1479+245A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
NPPA	ENST00000376480.7 linkuse as main transcript	c.454T>C	p.Ter152ArgextTer2	stop_lost	3/3	1	NM_006172.4	ENSP00000365663	P1
CLCN6	ENST00000446542.5 linkuse as main transcript	n.781+245A>G		intron_variant, non_coding_transcript_variant		1
NPPA	ENST00000376476.1 linkuse as main transcript	c.304T>C	p.Ter102ArgextTer2	stop_lost	3/3	3		ENSP00000365659
CLCN6	ENST00000400892.3 linkuse as main transcript	c.*1961+245A>G		intron_variant, NMD_transcript_variant		3		ENSP00000496938

Frequencies

GnomAD3 genomes

AF:

0.207

AC:

31395

AN:

151958

Hom.:

4465

Cov.:

show subpopulations

Gnomad AFR

AF:

0.403

Gnomad AMI

AF:

0.149

Gnomad AMR

AF:

0.139

Gnomad ASJ

AF:

0.120

Gnomad EAS

AF:

0.0106

Gnomad SAS

AF:

0.145

Gnomad FIN

AF:

0.0724

Gnomad MID

AF:

0.232

Gnomad NFE

AF:

0.148

Gnomad OTH

AF:

0.202

GnomAD3 exomes

AF:

0.137

AC:

34498

AN:

250974

Hom.:

3300

AF XY:

0.136

AC XY:

18436

AN XY:

135722

show subpopulations

Gnomad AFR exome

AF:

0.413

Gnomad AMR exome

AF:

0.0894

Gnomad ASJ exome

AF:

0.119

Gnomad EAS exome

AF:

0.0105

Gnomad SAS exome

AF:

0.156

Gnomad FIN exome

AF:

0.0768

Gnomad NFE exome

AF:

0.141

Gnomad OTH exome

AF:

0.145

GnomAD4 exome

AF:

0.147

AC:

214793

AN:

1461174

Hom.:

17759

Cov.:

AF XY:

0.147

AC XY:

107035

AN XY:

726952

show subpopulations

Gnomad4 AFR exome

AF:

0.415

Gnomad4 AMR exome

AF:

0.0951

Gnomad4 ASJ exome

AF:

0.121

Gnomad4 EAS exome

AF:

0.00982

Gnomad4 SAS exome

AF:

0.155

Gnomad4 FIN exome

AF:

0.0763

Gnomad4 NFE exome

AF:

0.149

Gnomad4 OTH exome

AF:

0.151

GnomAD4 genome

AF:

0.207

AC:

31425

AN:

152076

Hom.:

4472

Cov.:

AF XY:

0.203

AC XY:

15105

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.403

Gnomad4 AMR

AF:

0.138

Gnomad4 ASJ

AF:

0.120

Gnomad4 EAS

AF:

0.0106

Gnomad4 SAS

AF:

0.145

Gnomad4 FIN

AF:

0.0724

Gnomad4 NFE

AF:

0.148

Gnomad4 OTH

AF:

0.204

Alfa

AF:

0.156

Hom.:

5498

Bravo

AF:

0.219

TwinsUK

AF:

0.153

AC:

568

ALSPAC

AF:

0.138

AC:

533

ESP6500AA

AF:

0.409

AC:

1800

ESP6500EA

AF:

0.155

AC:

1335

ExAC

AF:

0.144

AC:

17445

Asia WGS

AF:

0.0990

AC:

346

AN:

3478

EpiCase

AF:

0.144

EpiControl

AF:

0.145

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jul 31, 2015	p.X152ArgextX3 in exon 3 of NPPA: This variant is not expected to have clinical significance since it has been identified in 40.1% (4244/10406) of African chrom osomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org ; dbSNP rs5065). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Apr 12, 2016	- -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 15, 2018	This variant is associated with the following publications: (PMID: 23529183, 22400494, 20543198, 17984371, 24041948, 19702001, 22575314, 25401746, 15017020, 29439446) -

Atrial fibrillation, familial, 6

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.46

CADD

Benign

DANN

Benign

0.79

Eigen

Uncertain

0.40

Eigen_PC

Benign

0.15

FATHMM_MKL

Benign

0.0012

MutationTaster

Benign

1.0

P;P

GERP RS

0.95

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