12-117220188-C-T

Variant names:

• chr12-117220188-C-T
• rs74427117
• NM_000620.5:c.4057G>A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_000620.5(NOS1):​c.4057G>A​(p.Val1353Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00129 in 1,613,978 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00087 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (3 hom.)
• Consequence: NOS1 NM_000620.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1 B:1
• Conservation: PhyloP100: 6.15

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.027145267).
• BS2: High AC in GnomAd4 at 132 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOS1	NM_000620.5	c.4057G>A	p.Val1353Ile	missense_variant	Exon 27 of 29	ENST00000317775.11	NP_000611.1
NOS1	NM_001204218.2	c.4159G>A	p.Val1387Ile	missense_variant	Exon 28 of 30		NP_001191147.1
NOS1	NM_001204213.2	c.3049G>A	p.Val1017Ile	missense_variant	Exon 26 of 28		NP_001191142.1
NOS1	NM_001204214.2	c.3049G>A	p.Val1017Ile	missense_variant	Exon 26 of 28		NP_001191143.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOS1	ENST00000317775.11	c.4057G>A	p.Val1353Ile	missense_variant	Exon 27 of 29	1	NM_000620.5	ENSP00000320758.6
NOS1	ENST00000338101.8	c.4159G>A	p.Val1387Ile	missense_variant	Exon 27 of 29	5		ENSP00000337459.4
NOS1	ENST00000618760.4	c.4159G>A	p.Val1387Ile	missense_variant	Exon 28 of 30	5		ENSP00000477999.1

Frequencies

GnomAD3 genomes AF: 0.000874 AC: 133 AN: 152224 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000386

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00147

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.000977 AC: 244 AN: 249704 Hom.: 1 AF XY: 0.00104 AC XY: 141 AN XY: 135262

Gnomad AFR exome AF: 0.000442

Gnomad AMR exome AF: 0.000261

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000167

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.000608

Gnomad NFE exome AF: 0.00182

Gnomad OTH exome AF: 0.000821

GnomAD4 exome AF: 0.00134 AC: 1957 AN: 1461636 Hom.: 3 Cov.: 31 AF XY: 0.00137 AC XY: 998 AN XY: 727140

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.000246

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.000151

Gnomad4 FIN exome AF: 0.000902

Gnomad4 NFE exome AF: 0.00165

Gnomad4 OTH exome AF: 0.000745

GnomAD4 genome AF: 0.000866 AC: 132 AN: 152342 Hom.: 0 Cov.: 32 AF XY: 0.000859 AC XY: 64 AN XY: 74494

Gnomad4 AFR AF: 0.000385

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.000565

Gnomad4 NFE AF: 0.00147

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00118 Hom.: 1

Bravo AF: 0.000718

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.00110 AC: 134

EpiCase AF: 0.00125

EpiControl AF: 0.00148

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 30, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4159G>A (p.V1387I) alteration is located in exon 28 (coding exon 27) of the NOS1 gene. This alteration results from a G to A substitution at nucleotide position 4159, causing the valine (V) at amino acid position 1387 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

NOS1-related disorder Benign:1

Jul 19, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.20
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.45	T;.;.;T
Eigen	Benign	-0.067
Eigen_PC	Benign	0.058
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.94	D;D;.;D
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.027	T;T;T;T
MetaSVM	Benign	-0.55	T
MutationAssessor	Benign	1.1	L;.;.;.
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.81	N;.;N;.
REVEL	Benign	0.23
Sift	Benign	0.069	T;.;T;.
Sift4G	Benign	0.075	T;T;T;T
Polyphen		0.14	B;.;.;.
Vest4		0.43
MVP		0.75
MPC		0.55
ClinPred		0.017	T
GERP RS		4.4
Varity_R		0.091
gMVP		0.56

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: rs74427117; hg19: chr12-117657993;