rs1475348735

Variant names:

• chr1-11847105-C-T
• rs1475348735
• NM_006172.4:c.450+8G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_006172.4(NPPA):​c.450+8G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000263 in 1,522,900 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: NPPA NM_006172.4 splice_region, intron
• Scores: Splicing: ADA: 0.001026
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.01
• 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: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 1-11847105-C-T is Benign according to our data. Variant chr1-11847105-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2901893.Status of the report is criteria_provided_single_submitter, 1 stars.

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+8G>A		splice_region intron	N/A	NP_006163.1	P01160
	NPPA-AS1	NR_037806.1		n.1480-329C>T		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+8G>A		splice_region intron	N/A	ENSP00000365663.3	P01160
	CLCN6	ENST00000446542.5	TSL:1	n.782-329C>T		intron	N/A
	NPPA	ENST00000376476.1	TSL:3	c.300+8G>A		splice_region intron	N/A	ENSP00000365659.1	B0ZBE8

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152164 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 7.30e-7 AC: 1 AN: 1370736 Hom.: 0 Cov.: 32 AF XY: 0.00000149 AC XY: 1 AN XY: 672130

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30460

American (AMR) AF: 0.00 AC: 0 AN: 30364

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20326

East Asian (EAS) AF: 0.00 AC: 0 AN: 38862

South Asian (SAS) AF: 0.0000140 AC: 1 AN: 71366

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48568

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5344

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1069026

Other (OTH) AF: 0.00 AC: 0 AN: 56420

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152164 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74326

African (AFR) AF: 0.0000724 AC: 3 AN: 41440

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Atrial fibrillation, familial, 6 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	13
DANN	Benign	0.88
PhyloP100		1.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0010
dbscSNV1_RF	Benign	0.0020
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: rs1475348735; hg19: chr1-11907162;