12-117227439-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 1P and 10B. PP2 BP4_Strong BP6_Moderate BS2

The NM_000620.5(NOS1):c.3608G>A(p.Arg1203His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000533 in 1,613,708 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000051 (0 hom.)
• Consequence: NOS1 NM_000620.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.67

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 -9 ACMG points.

• PP2: Missense variant where missense usually causes diseases, NOS1
• BP4: Computational evidence support a benign effect (MetaRNN=0.024298757).
• BP6: Variant 12-117227439-C-T is Benign according to our data. Variant chr12-117227439-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2375825.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOS1	NM_000620.5	c.3608G>A	p.Arg1203His	missense_variant	23/29	ENST00000317775.11
NOS1	NM_001204218.2	c.3710G>A	p.Arg1237His	missense_variant	24/30
NOS1	NM_001204213.2	c.2600G>A	p.Arg867His	missense_variant	22/28
NOS1	NM_001204214.2	c.2600G>A	p.Arg867His	missense_variant	22/28

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOS1	ENST00000317775.11	c.3608G>A	p.Arg1203His	missense_variant	23/29	1	NM_000620.5	P1
NOS1	ENST00000338101.8	c.3710G>A	p.Arg1237His	missense_variant	23/29	5
NOS1	ENST00000618760.4	c.3710G>A	p.Arg1237His	missense_variant	24/30	5

Frequencies

GnomAD3 genomes AF: 0.0000789 AC: 12 AN: 152158 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000153 AC: 38 AN: 248810 Hom.: 0 AF XY: 0.000126 AC XY: 17 AN XY: 134996

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000784

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000557

Gnomad SAS exome AF: 0.0000328

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000797

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000506 AC: 74 AN: 1461432 Hom.: 0 Cov.: 32 AF XY: 0.0000509 AC XY: 37 AN XY: 727014

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000672

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000306

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000788 AC: 12 AN: 152276 Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5 AN XY: 74454

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000139 Hom.: 0

Bravo AF: 0.000110

ExAC AF: 0.000182 AC: 22

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 12, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.50
Cadd	Benign	17
Dann	Benign	0.95
DEOGEN2	Uncertain	0.44	T;.;.;T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.79	T;T;.;T
M_CAP	Benign	0.0095	T
MetaRNN	Benign	0.024	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.84	L;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-1.9	N;.;N;.
REVEL	Benign	0.031
Sift	Benign	0.30	T;.;T;.
Sift4G	Benign	0.31	T;T;T;T
Polyphen		0.018	B;.;.;.
Vest4		0.099
MutPred		0.38		Gain of catalytic residue at S1201 (P = 0);.;.;.;
MVP		0.42
MPC		0.69
ClinPred		0.046	T
GERP RS		1.8
Varity_R		0.039
gMVP		0.31

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: rs571737466; hg19: chr12-117665244; COSMIC: COSV57623230;