chr1-162300673-G-A

Position:

• chr1-162300673-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_014697.3(NOS1AP):​c.311G>A​(p.Ser104Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00352 in 1,614,034 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0033 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0035 (15 hom.)
• Consequence: NOS1AP NM_014697.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.86

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009107232).
• BP6: Variant 1-162300673-G-A is Benign according to our data. Variant chr1-162300673-G-A is described in ClinVar as [Benign]. Clinvar id is 714274.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOS1AP	NM_014697.3	c.311G>A	p.Ser104Asn	missense_variant	4/10	ENST00000361897.10
NOS1AP	NM_001164757.2	c.296G>A	p.Ser99Asn	missense_variant	4/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOS1AP	ENST00000361897.10	c.311G>A	p.Ser104Asn	missense_variant	4/10	1	NM_014697.3
NOS1AP	ENST00000530878.5	c.296G>A	p.Ser99Asn	missense_variant	4/10	1		P1
NOS1AP	ENST00000430120.3	c.296G>A	p.Ser99Asn	missense_variant, NMD_transcript_variant	4/11	1

Frequencies

GnomAD3 genomes AF: 0.00331 AC: 503 AN: 152120 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.0184

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00379

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00340 AC: 854 AN: 251438 Hom.: 1 AF XY: 0.00346 AC XY: 470 AN XY: 135884

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000520

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00183

Gnomad FIN exome AF: 0.0153

Gnomad NFE exome AF: 0.00374

Gnomad OTH exome AF: 0.00326

GnomAD4 exome AF: 0.00355 AC: 5184 AN: 1461796 Hom.: 15 Cov.: 31 AF XY: 0.00357 AC XY: 2599 AN XY: 727190

Gnomad4 AFR exome AF: 0.000597

Gnomad4 AMR exome AF: 0.000604

Gnomad4 ASJ exome AF: 0.000115

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00206

Gnomad4 FIN exome AF: 0.0151

Gnomad4 NFE exome AF: 0.00360

Gnomad4 OTH exome AF: 0.00229

GnomAD4 genome AF: 0.00330 AC: 503 AN: 152238 Hom.: 2 Cov.: 32 AF XY: 0.00391 AC XY: 291 AN XY: 74442

Gnomad4 AFR AF: 0.000530

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00228

Gnomad4 FIN AF: 0.0184

Gnomad4 NFE AF: 0.00379

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00346 Hom.: 2

Bravo AF: 0.00215

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.00415 AC: 16

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00430 AC: 37

ExAC AF: 0.00330 AC: 400

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00354

EpiControl AF: 0.00267

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Apr 23, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	.;T
Eigen	Benign	-0.050
Eigen_PC	Benign	0.082
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.82	T;T
MetaRNN	Benign	0.0091	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.78	.;N
MutationTaster	Benign	0.97	D;D
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.27	N;N
REVEL	Benign	0.11
Sift	Benign	0.37	T;T
Sift4G	Benign	0.35	T;T
Polyphen		0.011	.;B
Vest4		0.084
MVP		0.31
MPC		1.1
ClinPred		0.0094	T
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.26
gMVP		0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs41271967; hg19: chr1-162270463;