1-11846903-T-C

Variant names:

• chr1-11846903-T-C
• rs198369
• NM_006172.4:c.450+210A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_006172.4(NPPA):​c.450+210A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.445 in 148,354 control chromosomes in the GnomAD database, including 15,528 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.45 (15528 hom., cov: 26)
• Consequence: NPPA NM_006172.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.21
• Publications: 4 publications found

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:37635): (NPPA antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BP6: Variant 1-11846903-T-C is Benign according to our data. Variant chr1-11846903-T-C is described in ClinVar as Benign. ClinVar VariationId is 1181476.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.57 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006172.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPPA	NM_006172.4	MANE Select	c.450+210A>G		intron	N/A	NP_006163.1	P01160
	NPPA-AS1	NR_037806.1		n.1480-531T>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPPA	ENST00000376480.7	TSL:1 MANE Select	c.450+210A>G		intron	N/A	ENSP00000365663.3	P01160
	CLCN6	ENST00000446542.5	TSL:1	n.782-531T>C		intron	N/A
	NPPA	ENST00000376476.1	TSL:3	c.300+210A>G		intron	N/A	ENSP00000365659.1	B0ZBE8

Frequencies

GnomAD3 genomes AF: 0.445 AC: 66016 AN: 148276 Hom.: 15503 Cov.: 26

Gnomad AFR AF: 0.575

Gnomad AMI AF: 0.398

Gnomad AMR AF: 0.316

Gnomad ASJ AF: 0.367

Gnomad EAS AF: 0.230

Gnomad SAS AF: 0.512

Gnomad FIN AF: 0.375

Gnomad MID AF: 0.516

Gnomad NFE AF: 0.422

Gnomad OTH AF: 0.438

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.445 AC: 66070 AN: 148354 Hom.: 15528 Cov.: 26 AF XY: 0.443 AC XY: 31872 AN XY: 71954

African (AFR) AF: 0.576 AC: 23200 AN: 40286

American (AMR) AF: 0.315 AC: 4714 AN: 14964

Ashkenazi Jewish (ASJ) AF: 0.367 AC: 1270 AN: 3464

East Asian (EAS) AF: 0.230 AC: 1147 AN: 4980

South Asian (SAS) AF: 0.513 AC: 2429 AN: 4738

European-Finnish (FIN) AF: 0.375 AC: 3438 AN: 9164

Middle Eastern (MID) AF: 0.503 AC: 146 AN: 290

European-Non Finnish (NFE) AF: 0.422 AC: 28452 AN: 67482

Other (OTH) AF: 0.439 AC: 913 AN: 2078

Alfa AF: 0.418 Hom.: 1675

Bravo AF: 0.443

Asia WGS AF: 0.386 AC: 1339 AN: 3474

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.47
DANN	Benign	0.69
PhyloP100		-2.2
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs198369; hg19: chr1-11906960;