1-11847602-A-T

Position:

• chr1-11847602-A-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4

The ENST00000376480.7(NPPA):​c.83T>A​(p.Met28Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000116 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M28T) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: NPPA ENST00000376480.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.894

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:):

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.31254217).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NPPA	NM_006172.4	c.83T>A	p.Met28Lys	missense_variant	1/3	ENST00000376480.7	NP_006163.1
NPPA-AS1	NR_037806.1	n.1648A>T		non_coding_transcript_exon_variant	4/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NPPA	ENST00000376480.7	c.83T>A	p.Met28Lys	missense_variant	1/3	1	NM_006172.4	ENSP00000365663	P1
CLCN6	ENST00000446542.5	n.950A>T		non_coding_transcript_exon_variant	4/4	1
NPPA	ENST00000376476.1	c.-27-163T>A		intron_variant		3		ENSP00000365659
CLCN6	ENST00000400892.3	c.*1987A>T		3_prime_UTR_variant, NMD_transcript_variant	27/27	3		ENSP00000496938

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000116 AC: 17 AN: 1461892 Hom.: 0 Cov.: 33 AF XY: 0.0000110 AC XY: 8 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000153

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000151

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	15
DANN	Benign	0.92
DEOGEN2	Benign	0.098	.;T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.59	.;T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.31	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-2.3	N;.
REVEL	Benign	0.12
Sift	Uncertain	0.0040	D;.
Sift4G	Uncertain	0.018	D;D
Vest4		0.29
MutPred		0.48		Gain of ubiquitination at M28 (P = 0.0185);Gain of ubiquitination at M28 (P = 0.0185);
MVP		0.52
MPC		0.028
ClinPred		0.21	T
GERP RS		4.8
gMVP		0.59

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

Publications

LitVar

Other links and lift over

dbSNP: rs142116829; hg19: chr1-11907659;