rs76090928

chr12-117330349-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2 BP4_Strong BP6_Very_Strong BS2

The NM_000620.5(NOS1):c.721G>A(p.Asp241Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00261 in 1,610,320 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0020 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (9 hom.)
• Consequence: NOS1 NM_000620.5 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 5.55

Genes affected

NOS1 (HGNC:7872): (nitric oxide synthase 1) The protein encoded by this gene belongs to the family of nitric oxide synthases, which synthesize nitric oxide from L-arginine. Nitric oxide is a reactive free radical, which acts as a biologic mediator in several processes, including neurotransmission, and antimicrobial and antitumoral activities. In the brain and peripheral nervous system, nitric oxide displays many properties of a neurotransmitter, and has been implicated in neurotoxicity associated with stroke and neurodegenerative diseases, neural regulation of smooth muscle, including peristalsis, and penile erection. This protein is ubiquitously expressed, with high level of expression in skeletal muscle. Multiple transcript variants that differ in the 5' UTR have been described for this gene but the full-length nature of these transcripts is not known. Additionally, alternatively spliced transcript variants encoding different isoforms (some testis-specific) have been found for this gene.[provided by RefSeq, Feb 2011]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• PP2: Missense variant where missense usually causes diseases, NOS1
• BP4: Computational evidence support a benign effect (MetaRNN=0.0079512).
• BP6: Variant 12-117330349-C-T is Benign according to our data. Variant chr12-117330349-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 790463.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd at 298 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOS1	NM_000620.5	c.721G>A	p.Asp241Asn	missense_variant	2/29	ENST00000317775.11
NOS1	NM_001204218.2	c.721G>A	p.Asp241Asn	missense_variant	2/30

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOS1	ENST00000317775.11	c.721G>A	p.Asp241Asn	missense_variant	2/29	1	NM_000620.5	P1
NOS1	ENST00000338101.8	c.721G>A	p.Asp241Asn	missense_variant	1/29	5
NOS1	ENST00000618760.4	c.721G>A	p.Asp241Asn	missense_variant	2/30	5

Frequencies

GnomAD3 genomes AF: 0.00196 AC: 298 AN: 151784 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000436

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00499

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000946

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00272

Gnomad OTH AF: 0.00336

GnomAD3 exomes AF: 0.00202 AC: 496 AN: 245606 Hom.: 1 AF XY: 0.00216 AC XY: 288 AN XY: 133130

Gnomad AFR exome AF: 0.000518

Gnomad AMR exome AF: 0.00306

Gnomad ASJ exome AF: 0.00513

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000101

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00274

Gnomad OTH exome AF: 0.00433

GnomAD4 exome AF: 0.00268 AC: 3909 AN: 1458422 Hom.: 9 Cov.: 33 AF XY: 0.00264 AC XY: 1914 AN XY: 725014

Gnomad4 AFR exome AF: 0.000598

Gnomad4 AMR exome AF: 0.00386

Gnomad4 ASJ exome AF: 0.00507

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000140

Gnomad4 FIN exome AF: 0.000225

Gnomad4 NFE exome AF: 0.00309

Gnomad4 OTH exome AF: 0.00209

GnomAD4 genome AF: 0.00196 AC: 298 AN: 151898 Hom.: 1 Cov.: 32 AF XY: 0.00183 AC XY: 136 AN XY: 74240

Gnomad4 AFR AF: 0.000435

Gnomad4 AMR AF: 0.00499

Gnomad4 ASJ AF: 0.00317

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000946

Gnomad4 NFE AF: 0.00272

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.00302 Hom.: 1

Bravo AF: 0.00277

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00403 AC: 34

ExAC AF: 0.00201 AC: 243

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

NOS1-related condition Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 29, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.63
Cadd	Uncertain	23
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.46	T;.;.;T
Eigen	Benign	0.18
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.74	T;T;.;T
M_CAP	Benign	0.0083	T
MetaRNN	Benign	0.0080	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L;L;L;.
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.1	N;.;N;.
REVEL	Benign	0.14
Sift	Benign	0.030	D;.;D;.
Sift4G	Uncertain	0.055	T;T;T;T
Polyphen		0.38	B;.;.;.
Vest4		0.30
MVP		0.48
MPC		0.26
ClinPred		0.019	T
GERP RS		4.7
Varity_R		0.15
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs76090928; hg19: chr12-117768154; COSMIC: COSV57613199; COSMIC: COSV57613199;