1-11847602-A-G

Position:

chr1-11847602-A-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_006172.4(NPPA):c.83T>C(p.Met28Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000372 in 1,614,112 control chromosomes in the GnomAD database, including 5 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0020 ( 3 hom., cov: 32)

Exomes 𝑓: 0.00021 ( 2 hom. )

Consequence

NPPA
NM_006172.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.894

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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.013659984).

BP6

Variant 1-11847602-A-G is Benign according to our data. Variant chr1-11847602-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 415934.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-11847602-A-G is described in Lovd as [Benign].

BS2

High Homozygotes in GnomAd4 at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPPA	NM_006172.4 linkuse as main transcript	c.83T>C	p.Met28Thr	missense_variant	1/3	ENST00000376480.7	NP_006163.1
NPPA-AS1	NR_037806.1 linkuse as main transcript	n.1648A>G		non_coding_transcript_exon_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
NPPA	ENST00000376480.7 linkuse as main transcript	c.83T>C	p.Met28Thr	missense_variant	1/3	1	NM_006172.4	ENSP00000365663	P1
CLCN6	ENST00000446542.5 linkuse as main transcript	n.950A>G		non_coding_transcript_exon_variant	4/4	1
NPPA	ENST00000376476.1 linkuse as main transcript	c.-27-163T>C		intron_variant		3		ENSP00000365659
CLCN6	ENST00000400892.3 linkuse as main transcript	c.*1987A>G		3_prime_UTR_variant, NMD_transcript_variant	27/27	3		ENSP00000496938

Frequencies

GnomAD3 genomes

AF:

0.00198

AC:

301

AN:

152102

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00688

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000851

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:

0.00

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.000549

AC:

138

AN:

251496

Hom.:

AF XY:

0.000478

AC XY:

AN XY:

135922

show subpopulations

Gnomad AFR exome

AF:

0.00701

Gnomad AMR exome

AF:

0.000636

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000205

AC:

300

AN:

1461892

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

137

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.00705

Gnomad4 AMR exome

AF:

0.000671

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000899

Gnomad4 OTH exome

AF:

0.000381

GnomAD4 genome

AF:

0.00198

AC:

301

AN:

152220

Hom.:

Cov.:

AF XY:

0.00188

AC XY:

140

AN XY:

74432

show subpopulations

Gnomad4 AFR

AF:

0.00686

Gnomad4 AMR

AF:

0.000850

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.000269

Hom.:

Bravo

AF:

0.00227

ESP6500AA

AF:

0.00635

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000684

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Jan 15, 2018

Variant summary: The NPPA c.83T>C (p.Met28Thr) variant involves the alteration of a non-conserved nucleotide. 2/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 181/277216 control chromosomes (1 homozygote) from all ethnicities, but was predominantly observed in the African subpopulation at a frequency of 0.006452 (155/24022; 1 homozygote). This frequency is about 645 times the estimated maximal expected allele frequency of a pathogenic NPPA variant (0.00001), suggesting this is likely a benign polymorphism found primarily in the populations of African origin. One clinical diagnostic laboratory classified this variant as likely benign. In addition, an internal LCA sample carries this variant along with a pathogenic KCNQ1 variant (c.727C>T, p.R243C). The variant of interest has not, to our knowledge, been reported in affected individuals via publications, nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign. -

Atrial fibrillation, familial, 6

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.62

CADD

Benign

DANN

Benign

0.81

DEOGEN2

Benign

0.028

.;T

Eigen

Benign

-0.61

Eigen_PC

Benign

-0.53

FATHMM_MKL

Benign

0.28

LIST_S2

Benign

0.53

.;T

M_CAP

Benign

0.013

MetaRNN

Benign

0.014

T;T

MetaSVM

Benign

-1.1

MutationTaster

Benign

1.0

D;N

PrimateAI

Benign

0.31

PROVEAN

Benign

-1.3

N;.

REVEL

Benign

0.096

Sift

Uncertain

0.014

D;.

Sift4G

Benign

0.075

T;T

Vest4

0.22

MVP

0.46

MPC

0.023

ClinPred

0.015

GERP RS

4.8

gMVP

0.40

Splicing

Name

Calibrated prediction

Score

Prediction

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