12-117232109-G-C

Variant names:

• chr12-117232109-G-C
• rs3741475
• NM_000620.5:c.3258C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000620.5(NOS1):​c.3258C>G​(p.Asp1086Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. D1086D) has been classified as Benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: NOS1 NM_000620.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.259
• Publications: 0 publications found

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]

NOS1 Gene-Disease associations (from GenCC):

• idiopathic achalasia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25453502).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOS1	NM_000620.5	c.3258C>G	p.Asp1086Glu	missense_variant	Exon 22 of 29	ENST00000317775.11	NP_000611.1
NOS1	NM_001204218.2	c.3360C>G	p.Asp1120Glu	missense_variant	Exon 23 of 30		NP_001191147.1
NOS1	NM_001204213.2	c.2250C>G	p.Asp750Glu	missense_variant	Exon 21 of 28		NP_001191142.1
NOS1	NM_001204214.2	c.2250C>G	p.Asp750Glu	missense_variant	Exon 21 of 28		NP_001191143.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOS1	ENST00000317775.11	c.3258C>G	p.Asp1086Glu	missense_variant	Exon 22 of 29	1	NM_000620.5	ENSP00000320758.6
NOS1	ENST00000338101.8	c.3360C>G	p.Asp1120Glu	missense_variant	Exon 22 of 29	5		ENSP00000337459.4
NOS1	ENST00000618760.4	c.3360C>G	p.Asp1120Glu	missense_variant	Exon 23 of 30	5		ENSP00000477999.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	0.054
DANN	Benign	0.56
DEOGEN2	Benign	0.30	T;.;.;T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.69	T;T;.;T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.25	T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	1.1	L;.;.;.
PhyloP100		-0.26
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.88	N;.;N;.
REVEL	Benign	0.093
Sift	Benign	0.90	T;.;T;.
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.0010	B;.;.;.
Vest4		0.18
MutPred		0.42		Gain of catalytic residue at P1091 (P = 2e-04);.;.;.;
MVP		0.45
MPC		0.52
ClinPred		0.15	T
GERP RS		-5.2
Varity_R		0.049
gMVP		0.26
Mutation Taster		=87/13	polymorphism

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

Other links and lift over

dbSNP: rs3741475; hg19: chr12-117669914;