chr1-11847114-C-T

Position:

chr1-11847114-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The ENST00000376480.7(NPPA):c.449G>A(p.Arg150Gln) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000212 in 1,528,966 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R150W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00022 ( 2 hom. )

Consequence

NPPA
ENST00000376480.7 missense, splice_region

Scores

Splicing: ADA: 0.9455

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1B:1

Conservation

PhyloP100: 4.61

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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.058746427).

BP6

Variant 1-11847114-C-T is Benign according to our data. Variant chr1-11847114-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 126846.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

BS2

High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPPA	NM_006172.4 linkuse as main transcript	c.449G>A	p.Arg150Gln	missense_variant, splice_region_variant	2/3	ENST00000376480.7	NP_006163.1
NPPA-AS1	NR_037806.1 linkuse as main transcript	n.1480-320C>T		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.449G>A	p.Arg150Gln	missense_variant, splice_region_variant	2/3	1	NM_006172.4	ENSP00000365663	P1
CLCN6	ENST00000446542.5 linkuse as main transcript	n.782-320C>T		intron_variant, non_coding_transcript_variant		1
NPPA	ENST00000376476.1 linkuse as main transcript	c.299G>A	p.Arg100Gln	missense_variant, splice_region_variant	2/3	3		ENSP00000365659
CLCN6	ENST00000400892.3 linkuse as main transcript	c.*1962-463C>T		intron_variant, NMD_transcript_variant		3		ENSP00000496938

Frequencies

GnomAD3 genomes

AF:

0.000171

AC:

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000353

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000222

AC:

AN:

185062

Hom.:

AF XY:

0.000152

AC XY:

AN XY:

98518

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00129

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000615

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000102

Gnomad OTH exome

AF:

0.000465

GnomAD4 exome

AF:

0.000216

AC:

298

AN:

1376688

Hom.:

Cov.:

AF XY:

0.000200

AC XY:

135

AN XY:

675786

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000872

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000244

Gnomad4 OTH exome

AF:

0.000177

GnomAD4 genome

AF:

0.000171

AC:

AN:

152278

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74466

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000353

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000559

Hom.:

Bravo

AF:

0.000200

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000355

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Atrial standstill 2

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 2013

- -

Atrial fibrillation, familial, 6

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 13, 2024

This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 150 of the NPPA protein (p.Arg150Gln). This variant is present in population databases (rs202102042, gnomAD 0.1%), and has an allele count higher than expected for a pathogenic variant. This missense change has been observed in individual(s) with clinical features of autosomal recessive atrial dilated cardiomyopathy (PMID: 23275345). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 126846). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Feb 10, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Uncertain

0.036

BayesDel_noAF

Pathogenic

0.23

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.24

.;T;.

Eigen

Pathogenic

0.79

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.87

.;D;D

M_CAP

Benign

0.064

MetaRNN

Benign

0.059

T;T;T

MetaSVM

Uncertain

0.18

MutationTaster

Benign

0.96

D;D

PrimateAI

Uncertain

0.54

PROVEAN

Uncertain

-3.1

D;.;D

REVEL

Uncertain

0.40

Sift

Pathogenic

0.0

D;.;D

Sift4G

Uncertain

0.011

D;D;D

Vest4

0.58

MVP

0.97

MPC

0.19

ClinPred

0.23

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.23

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.95

dbscSNV1_RF

Benign

0.67

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

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