rs348624

Variant names:

• chr1-162365466-C-T
• rs348624
• NM_014697.3:c.1002C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_014697.3(NOS1AP):​c.1002C>T​(p.Arg334Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.141 in 1,613,774 control chromosomes in the GnomAD database, including 20,644 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (4519 hom., cov: 33)
  • Exomes 𝑓: 0.13 (16125 hom.)
• Consequence: NOS1AP NM_014697.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.73
• Publications: 23 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)

ENSG00000254706 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.3).
• BP6: Variant 1-162365466-C-T is Benign according to our data. Variant chr1-162365466-C-T is described in ClinVar as Benign. ClinVar VariationId is 1233083.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.73 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.401 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOS1AP	NM_014697.3	c.1002C>T	p.Arg334Arg	synonymous_variant	Exon 9 of 10	ENST00000361897.10	NP_055512.1
NOS1AP	NM_001164757.2	c.987C>T	p.Arg329Arg	synonymous_variant	Exon 9 of 10		NP_001158229.1
NOS1AP	NM_001126060.2	c.117C>T	p.Arg39Arg	synonymous_variant	Exon 1 of 2		NP_001119532.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOS1AP	ENST00000361897.10	c.1002C>T	p.Arg334Arg	synonymous_variant	Exon 9 of 10	1	NM_014697.3	ENSP00000355133.5

Frequencies

GnomAD3 genomes AF: 0.206 AC: 31271 AN: 152030 Hom.: 4502 Cov.: 33

Gnomad AFR AF: 0.407

Gnomad AMI AF: 0.117

Gnomad AMR AF: 0.169

Gnomad ASJ AF: 0.145

Gnomad EAS AF: 0.140

Gnomad SAS AF: 0.265

Gnomad FIN AF: 0.116

Gnomad MID AF: 0.199

Gnomad NFE AF: 0.112

Gnomad OTH AF: 0.184

GnomAD2 exomes AF: 0.169 AC: 42412 AN: 250858 AF XY: 0.167

Gnomad AFR exome AF: 0.418

Gnomad AMR exome AF: 0.207

Gnomad ASJ exome AF: 0.154

Gnomad EAS exome AF: 0.131

Gnomad FIN exome AF: 0.108

Gnomad NFE exome AF: 0.117

Gnomad OTH exome AF: 0.145

GnomAD4 exome AF: 0.134 AC: 196212 AN: 1461626 Hom.: 16125 Cov.: 39 AF XY: 0.138 AC XY: 100044 AN XY: 727150

African (AFR) AF: 0.419 AC: 14043 AN: 33480

American (AMR) AF: 0.202 AC: 9041 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.147 AC: 3836 AN: 26134

East Asian (EAS) AF: 0.129 AC: 5136 AN: 39700

South Asian (SAS) AF: 0.260 AC: 22436 AN: 86256

European-Finnish (FIN) AF: 0.108 AC: 5737 AN: 53174

Middle Eastern (MID) AF: 0.183 AC: 1057 AN: 5766

European-Non Finnish (NFE) AF: 0.113 AC: 125806 AN: 1112000

Other (OTH) AF: 0.151 AC: 9120 AN: 60392

GnomAD4 genome AF: 0.206 AC: 31322 AN: 152148 Hom.: 4519 Cov.: 33 AF XY: 0.207 AC XY: 15399 AN XY: 74394

African (AFR) AF: 0.407 AC: 16861 AN: 41468

American (AMR) AF: 0.169 AC: 2579 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.145 AC: 505 AN: 3472

East Asian (EAS) AF: 0.139 AC: 721 AN: 5172

South Asian (SAS) AF: 0.266 AC: 1282 AN: 4822

European-Finnish (FIN) AF: 0.116 AC: 1224 AN: 10592

Middle Eastern (MID) AF: 0.194 AC: 57 AN: 294

European-Non Finnish (NFE) AF: 0.112 AC: 7595 AN: 68014

Other (OTH) AF: 0.185 AC: 392 AN: 2116

Alfa AF: 0.149 Hom.: 3450

Bravo AF: 0.219

Asia WGS AF: 0.233 AC: 810 AN: 3478

EpiCase AF: 0.123

EpiControl AF: 0.127

ClinVar

Significance: Benign

Submissions summary: Benign:3

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

- -

Feb 28, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nephrotic syndrome, type 22 Benign:1

Aug 14, 2021

Fulgent Genetics, Fulgent Genetics

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	-0.30
CADD	Benign	0.86
DANN	Benign	0.82
PhyloP100		-2.7
PromoterAI		-0.0042	Neutral
Mutation Taster		=94/6	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: rs348624; hg19: chr1-162335256; COSMIC: COSV62633145; COSMIC: COSV62633145;