1-11845917-A-T

Variant names:

• chr1-11845917-A-T
• rs5068
• NM_006172.4:c.*92T>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_006172.4(NPPA):​c.*92T>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000908 in 1,101,534 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: 9.1e-7 (0 hom.)
• Consequence: NPPA NM_006172.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.517
• Publications: 112 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)

ENSG00000278852 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NPPA	NM_006172.4	c.*92T>A		3_prime_UTR_variant	Exon 3 of 3	ENST00000376480.7	NP_006163.1
NPPA-AS1	NR_037806.1	n.1479+151A>T		intron_variant	Intron 3 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NPPA	ENST00000376480.7	c.*92T>A		3_prime_UTR_variant	Exon 3 of 3	1	NM_006172.4	ENSP00000365663.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 9.08e-7 AC: 1 AN: 1101534 Hom.: 0 Cov.: 15 AF XY: 0.00 AC XY: 0 AN XY: 565062

African (AFR) AF: 0.00 AC: 0 AN: 26142

American (AMR) AF: 0.00 AC: 0 AN: 44240

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23876

East Asian (EAS) AF: 0.00 AC: 0 AN: 38088

South Asian (SAS) AF: 0.00 AC: 0 AN: 79180

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53262

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5094

European-Non Finnish (NFE) AF: 0.00000128 AC: 1 AN: 783214

Other (OTH) AF: 0.00 AC: 0 AN: 48438

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 310

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	3.7
DANN	Benign	0.71
PhyloP100		0.52

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: rs5068; hg19: chr1-11905974;