NM_006172.4:c.*258_*268delGTTTGAAAGTG

Variant names:

• chr1-11845740-TCACTTTCAAAC-T
• rs63749086
• NM_006172.4:c.*258_*268delGTTTGAAAGTG

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_006172.4(NPPA):​c.*258_*268delGTTTGAAAGTG variant causes a 3 prime UTR change. The variant allele was found at a frequency of 0.046 in 545,770 control chromosomes in the GnomAD database, including 710 homozygotes. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.041 (172 hom., cov: 32)
  • Exomes 𝑓: 0.048 (538 hom.)
• Consequence: NPPA NM_006172.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.25
• Publications: 1 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 -10 ACMG points.

• BP6: Variant 1-11845740-TCACTTTCAAAC-T is Benign according to our data. Variant chr1-11845740-TCACTTTCAAAC-T is described in ClinVar as Benign. ClinVar VariationId is 1276720.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0594 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPPA	NM_006172.4	MANE Select	c.*258_*268delGTTTGAAAGTG		3_prime_UTR	Exon 3 of 3	NP_006163.1	P01160
	NPPA-AS1	NR_037806.1		n.1462_1472delAACCACTTTCA		non_coding_transcript_exon	Exon 3 of 4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NPPA	ENST00000376480.7	TSL:1 MANE Select	c.*258_*268delGTTTGAAAGTG		3_prime_UTR	Exon 3 of 3	ENSP00000365663.3	P01160
	CLCN6	ENST00000446542.5	TSL:1	n.764_774delAACCACTTTCA		non_coding_transcript_exon	Exon 3 of 4
	NPPA	ENST00000953330.1		c.*258_*268delGTTTGAAAGTG		3_prime_UTR	Exon 2 of 2	ENSP00000623389.1

Frequencies

GnomAD3 genomes AF: 0.0409 AC: 6227 AN: 152184 Hom.: 172 Cov.: 32

Gnomad AFR AF: 0.0116

Gnomad AMI AF: 0.0504

Gnomad AMR AF: 0.0405

Gnomad ASJ AF: 0.0683

Gnomad EAS AF: 0.00212

Gnomad SAS AF: 0.0480

Gnomad FIN AF: 0.0325

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0609

Gnomad OTH AF: 0.0431

GnomAD4 exome AF: 0.0481 AC: 18907 AN: 393468 Hom.: 538 AF XY: 0.0486 AC XY: 10031 AN XY: 206220

African (AFR) AF: 0.0128 AC: 148 AN: 11538

American (AMR) AF: 0.0343 AC: 605 AN: 17644

Ashkenazi Jewish (ASJ) AF: 0.0610 AC: 738 AN: 12108

East Asian (EAS) AF: 0.00527 AC: 151 AN: 28632

South Asian (SAS) AF: 0.0419 AC: 1580 AN: 37752

European-Finnish (FIN) AF: 0.0340 AC: 871 AN: 25610

Middle Eastern (MID) AF: 0.0837 AC: 143 AN: 1708

European-Non Finnish (NFE) AF: 0.0578 AC: 13608 AN: 235380

Other (OTH) AF: 0.0460 AC: 1063 AN: 23096

GnomAD4 genome AF: 0.0409 AC: 6222 AN: 152302 Hom.: 172 Cov.: 32 AF XY: 0.0407 AC XY: 3029 AN XY: 74474

African (AFR) AF: 0.0115 AC: 480 AN: 41578

American (AMR) AF: 0.0404 AC: 617 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0683 AC: 237 AN: 3472

East Asian (EAS) AF: 0.00212 AC: 11 AN: 5186

South Asian (SAS) AF: 0.0476 AC: 230 AN: 4828

European-Finnish (FIN) AF: 0.0325 AC: 345 AN: 10614

Middle Eastern (MID) AF: 0.0748 AC: 22 AN: 294

European-Non Finnish (NFE) AF: 0.0609 AC: 4144 AN: 68020

Other (OTH) AF: 0.0426 AC: 90 AN: 2112

Alfa AF: 0.0411 Hom.: 22

Bravo AF: 0.0400

Asia WGS AF: 0.0260 AC: 92 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.3
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs63749086; hg19: chr1-11905797; COSMIC: COSV56740434; COSMIC: COSV56740434;