1-11845924-A-G

Variant names:

• chr1-11845924-A-G
• rs5067
• NM_006172.4:c.*85T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006172.4(NPPA):​c.*85T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.148 in 1,338,838 control chromosomes in the GnomAD database, including 18,007 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (4477 hom., cov: 32)
  • Exomes 𝑓: 0.14 (13530 hom.)
• Consequence: NPPA NM_006172.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.638
• Publications: 31 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 1-11845924-A-G is Benign according to our data. Variant chr1-11845924-A-G is described in ClinVar as Benign. ClinVar VariationId is 1233521.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.398 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPPA	NM_006172.4	MANE Select	c.*85T>C		3_prime_UTR	Exon 3 of 3	NP_006163.1
	NPPA-AS1	NR_037806.1		n.1479+158A>G		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPPA	ENST00000376480.7	TSL:1 MANE Select	c.*85T>C		3_prime_UTR	Exon 3 of 3	ENSP00000365663.3
	CLCN6	ENST00000446542.5	TSL:1	n.781+158A>G		intron	N/A
	NPPA	ENST00000376476.1	TSL:3	c.*85T>C		3_prime_UTR	Exon 3 of 3	ENSP00000365659.1

Frequencies

GnomAD3 genomes AF: 0.207 AC: 31416 AN: 152046 Hom.: 4470 Cov.: 32

Gnomad AFR AF: 0.403

Gnomad AMI AF: 0.149

Gnomad AMR AF: 0.139

Gnomad ASJ AF: 0.121

Gnomad EAS AF: 0.0106

Gnomad SAS AF: 0.145

Gnomad FIN AF: 0.0730

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.148

Gnomad OTH AF: 0.201

GnomAD4 exome AF: 0.141 AC: 166805 AN: 1186674 Hom.: 13530 Cov.: 16 AF XY: 0.141 AC XY: 85375 AN XY: 603886

African (AFR) AF: 0.404 AC: 11197 AN: 27704

American (AMR) AF: 0.0948 AC: 4203 AN: 44344

Ashkenazi Jewish (ASJ) AF: 0.120 AC: 2926 AN: 24410

East Asian (EAS) AF: 0.00969 AC: 373 AN: 38500

South Asian (SAS) AF: 0.154 AC: 12438 AN: 80836

European-Finnish (FIN) AF: 0.0761 AC: 4054 AN: 53278

Middle Eastern (MID) AF: 0.252 AC: 1317 AN: 5230

European-Non Finnish (NFE) AF: 0.143 AC: 122761 AN: 861006

Other (OTH) AF: 0.147 AC: 7536 AN: 51366

GnomAD4 genome AF: 0.207 AC: 31446 AN: 152164 Hom.: 4477 Cov.: 32 AF XY: 0.203 AC XY: 15111 AN XY: 74396

African (AFR) AF: 0.403 AC: 16717 AN: 41478

American (AMR) AF: 0.138 AC: 2117 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.121 AC: 418 AN: 3466

East Asian (EAS) AF: 0.0106 AC: 55 AN: 5182

South Asian (SAS) AF: 0.145 AC: 697 AN: 4822

European-Finnish (FIN) AF: 0.0730 AC: 775 AN: 10610

Middle Eastern (MID) AF: 0.241 AC: 71 AN: 294

European-Non Finnish (NFE) AF: 0.148 AC: 10032 AN: 67990

Other (OTH) AF: 0.203 AC: 428 AN: 2108

Alfa AF: 0.185 Hom.: 1566

Bravo AF: 0.219

Asia WGS AF: 0.0990 AC: 346 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Sep 04, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.54
DANN	Benign	0.56
PhyloP100		-0.64
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: rs5067; hg19: chr1-11905981;