rs5063

chr1-11847591-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.360

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]

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]

NPPA-AS1 (HGNC:):

ACMG classification

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	UniProt
NPPA	NM_006172.4	c.94G>A	p.Val32Met	missense_variant	1/3	ENST00000376480.7
NPPA-AS1	NR_037806.1	n.1637C>T		non_coding_transcript_exon_variant	4/4

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.0538 AC: 8183 AN: 152082 Hom.: 278 Cov.: 32

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

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.: 33 AF XY: 0.0549 AC XY: 39917 AN XY: 727236

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.: 32 AF XY: 0.0533 AC XY: 3967 AN XY: 74398

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:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Atrial fibrillation, familial, 6 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

not provided Benign:1

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) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.71
Cadd	Benign	2.9
Dann	Benign	0.82
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.034	N
MetaRNN	Benign	0.0020	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;N
PrimateAI	Benign	0.37	T
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	T
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

Other links and lift over

dbSNP: rs5063; hg19: chr1-11907648; COSMIC: COSV56738708; COSMIC: COSV56738708;