12-117220098-C-T

Variant names:

• chr12-117220098-C-T
• rs757580443
• NM_000620.5:c.4147G>A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_000620.5(NOS1):​c.4147G>A​(p.Gly1383Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000931 in 1,611,272 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: NOS1 NM_000620.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U: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 Likely_benign. Variant got -4 ACMG points.

• BS2: High AC in GnomAdExome4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOS1	NM_000620.5	c.4147G>A	p.Gly1383Ser	missense_variant	Exon 27 of 29	ENST00000317775.11	NP_000611.1
NOS1	NM_001204218.2	c.4249G>A	p.Gly1417Ser	missense_variant	Exon 28 of 30		NP_001191147.1
NOS1	NM_001204213.2	c.3139G>A	p.Gly1047Ser	missense_variant	Exon 26 of 28		NP_001191142.1
NOS1	NM_001204214.2	c.3139G>A	p.Gly1047Ser	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.4147G>A	p.Gly1383Ser	missense_variant	Exon 27 of 29	1	NM_000620.5	ENSP00000320758.6
NOS1	ENST00000338101.8	c.4249G>A	p.Gly1417Ser	missense_variant	Exon 27 of 29	5		ENSP00000337459.4
NOS1	ENST00000618760.4	c.4249G>A	p.Gly1417Ser	missense_variant	Exon 28 of 30	5		ENSP00000477999.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152186 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000163 AC: 4 AN: 245966 Hom.: 0 AF XY: 0.0000225 AC XY: 3 AN XY: 133386

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000294

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000561

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000896

Gnomad OTH exome AF: 0.000168

GnomAD4 exome AF: 0.00000822 AC: 12 AN: 1459086 Hom.: 0 Cov.: 31 AF XY: 0.00000965 AC XY: 7 AN XY: 725734

Gnomad4 AFR exome AF: 0.0000898

Gnomad4 AMR exome AF: 0.0000225

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000467

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152186 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74356

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 19, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4249G>A (p.G1417S) 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 4249, causing the glycine (G) at amino acid position 1417 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	23
DANN	Benign	0.88
DEOGEN2	Benign	0.36	T;.;.;T
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	D;D;.;D
M_CAP	Benign	0.060	D
MetaRNN	Uncertain	0.55	D;D;D;D
MetaSVM	Benign	-0.35	T
MutationAssessor	Benign	1.6	L;.;.;.
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.9	N;.;N;.
REVEL	Uncertain	0.40
Sift	Benign	0.47	T;.;T;.
Sift4G	Benign	0.57	T;T;T;T
Polyphen		0.93	P;.;.;.
Vest4		0.51
MutPred		0.46		Gain of catalytic residue at R1388 (P = 0.0205);.;.;.;
MVP		0.79
MPC		0.81
ClinPred		0.28	T
GERP RS		4.4
Varity_R		0.15
gMVP		0.62

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: rs757580443; hg19: chr12-117657903;