NM_014697.3:c.345-118C>T

Variant names:

• chr1-162332899-C-T
• rs347307
• NM_014697.3:c.345-118C>T

Variant summary

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

The NM_014697.3(NOS1AP):​c.345-118C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.478 in 754,940 control chromosomes in the GnomAD database, including 91,174 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.44 (15721 hom., cov: 32)
  • Exomes 𝑓: 0.49 (75453 hom.)
• Consequence: NOS1AP NM_014697.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0770
• Publications: 9 publications found

Genes affected

NOS1AP (HGNC:16859): (nitric oxide synthase 1 adaptor protein) This gene encodes a cytosolic protein that binds to the signaling molecule, neuronal nitric oxide synthase (nNOS). This protein has a C-terminal PDZ-binding domain that mediates interactions with nNOS and an N-terminal phosphotyrosine binding (PTB) domain that binds to the small monomeric G protein, Dexras1. Studies of the related mouse and rat proteins have shown that this protein functions as an adapter protein linking nNOS to specific targets, such as Dexras1 and the synapsins. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Sep 2009]

NOS1AP Gene-Disease associations (from GenCC):

• nephrotic syndrome, type 22

  Inheritance: AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 1-162332899-C-T is Benign according to our data. Variant chr1-162332899-C-T is described in ClinVar as [Benign]. Clinvar id is 1293317.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.548 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOS1AP	NM_014697.3	c.345-118C>T		intron_variant	Intron 4 of 9	ENST00000361897.10	NP_055512.1
NOS1AP	NM_001164757.2	c.330-118C>T		intron_variant	Intron 4 of 9		NP_001158229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOS1AP	ENST00000361897.10	c.345-118C>T		intron_variant	Intron 4 of 9	1	NM_014697.3	ENSP00000355133.5
NOS1AP	ENST00000530878.5	c.330-118C>T		intron_variant	Intron 4 of 9	1		ENSP00000431586.1
NOS1AP	ENST00000430120.3	n.330-118C>T		intron_variant	Intron 4 of 10	1		ENSP00000396713.3

Frequencies

GnomAD3 genomes AF: 0.438 AC: 66479 AN: 151878 Hom.: 15720 Cov.: 32

Gnomad AFR AF: 0.274

Gnomad AMI AF: 0.372

Gnomad AMR AF: 0.451

Gnomad ASJ AF: 0.471

Gnomad EAS AF: 0.217

Gnomad SAS AF: 0.340

Gnomad FIN AF: 0.460

Gnomad MID AF: 0.560

Gnomad NFE AF: 0.552

Gnomad OTH AF: 0.470

GnomAD4 exome AF: 0.488 AC: 294086 AN: 602944 Hom.: 75453 AF XY: 0.482 AC XY: 157132 AN XY: 325850

African (AFR) AF: 0.275 AC: 4576 AN: 16640

American (AMR) AF: 0.452 AC: 16235 AN: 35886

Ashkenazi Jewish (ASJ) AF: 0.474 AC: 9526 AN: 20096

East Asian (EAS) AF: 0.214 AC: 7129 AN: 33314

South Asian (SAS) AF: 0.348 AC: 22427 AN: 64400

European-Finnish (FIN) AF: 0.469 AC: 20312 AN: 43342

Middle Eastern (MID) AF: 0.470 AC: 1923 AN: 4090

European-Non Finnish (NFE) AF: 0.557 AC: 196784 AN: 353388

Other (OTH) AF: 0.477 AC: 15174 AN: 31788

GnomAD4 genome AF: 0.437 AC: 66482 AN: 151996 Hom.: 15721 Cov.: 32 AF XY: 0.430 AC XY: 31956 AN XY: 74274

African (AFR) AF: 0.274 AC: 11342 AN: 41466

American (AMR) AF: 0.450 AC: 6874 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.471 AC: 1635 AN: 3468

East Asian (EAS) AF: 0.216 AC: 1119 AN: 5170

South Asian (SAS) AF: 0.340 AC: 1639 AN: 4822

European-Finnish (FIN) AF: 0.460 AC: 4849 AN: 10544

Middle Eastern (MID) AF: 0.571 AC: 168 AN: 294

European-Non Finnish (NFE) AF: 0.552 AC: 37529 AN: 67936

Other (OTH) AF: 0.467 AC: 988 AN: 2114

Alfa AF: 0.490 Hom.: 2334

Bravo AF: 0.433

Asia WGS AF: 0.308 AC: 1073 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 06, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	4.3
DANN	Benign	0.32
PhyloP100		-0.077
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: rs347307; hg19: chr1-162302689; COSMIC: COSV62635284;