Genetic Variant NM_006172.4:c.456_*1delAA (chr1-11846007-CTT-C) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2PM4PP5

The NM_006172.4(NPPA):c.456_*1delAA(p.Ter152fs) variant causes a frameshift, stop lost change. The variant allele was found at a frequency of 0.000000684 in 1,461,820 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

NPPA
NM_006172.4 frameshift, stop_lost

Scores

Not classified

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 3.64

Publications

0 publications found

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:37635): (NPPA antisense RNA 1)

NPPA-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM4

Stoplost variant in NM_006172.4

PP5

Variant 1-11846007-CTT-C is Pathogenic according to our data. Variant chr1-11846007-CTT-C is described in ClinVar as [Pathogenic]. Clinvar id is 17788.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPPA	NM_006172.4 link	c.456_*1delAA	p.Ter152fs	frameshift_variant, stop_lost	Exon 3 of 3	ENST00000376480.7	NP_006163.1	P01160
NPPA	NM_006172.4 link	c.456_*1delAA		3_prime_UTR_variant	Exon 3 of 3	ENST00000376480.7	NP_006163.1	P01160
NPPA-AS1	NR_037806.1 link	n.1479+242_1479+243delTT		intron_variant	Intron 3 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPPA	ENST00000376480.7 link	c.456_*1delAA	p.Ter152fs	frameshift_variant, stop_lost	Exon 3 of 3	1	NM_006172.4	ENSP00000365663.3		P01160
NPPA	ENST00000376480.7 link	c.456_*1delAA		3_prime_UTR_variant	Exon 3 of 3	1	NM_006172.4	ENSP00000365663.3		P01160

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461820

Hom.:

AF XY:

0.00

AC XY:

AN XY:

727218

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33472

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111968

Other (OTH)

AF:

0.0000166

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Atrial fibrillation, familial, 6

Pathogenic:1

Jul 10, 2008

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

3.6

Mutation Taster

=21/179

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over