NM_006172.4:c.454T>A

Variant names:

• chr1-11846011-A-T
• rs5065
• NM_006172.4:c.454T>A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PM4 PP3

The NM_006172.4(NPPA):​c.454T>A​(p.Ter152Argext*?) variant causes a stop lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,732 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NPPA NM_006172.4 stop_lost
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.328
• Publications: 0 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: 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 Downstream stopcodon found after 184 codons.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPPA	NM_006172.4	MANE Select	c.454T>A	p.Ter152Argext*?	stop_lost	Exon 3 of 3	NP_006163.1
	NPPA-AS1	NR_037806.1		n.1479+245A>T		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPPA	ENST00000376480.7	TSL:1 MANE Select	c.454T>A	p.Ter152Argext*?	stop_lost	Exon 3 of 3	ENSP00000365663.3
	CLCN6	ENST00000446542.5	TSL:1	n.781+245A>T		intron	N/A
	NPPA	ENST00000376476.1	TSL:3	c.304T>A	p.Ter102Argext*?	stop_lost	Exon 3 of 3	ENSP00000365659.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461732 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727188

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111886

Other (OTH) AF: 0.00 AC: 0 AN: 60382

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	17
DANN	Benign	0.78
Eigen	Uncertain	0.40
Eigen_PC	Benign	0.15
FATHMM_MKL	Benign	0.038	N
PhyloP100		0.33
GERP RS		0.95
Mutation Taster		=180/20	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.69		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.69		Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs5065; hg19: chr1-11906068;