12-117222782-T-C

Variant names:

• chr12-117222782-T-C
• NM_000620.5:c.3908A>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000620.5(NOS1):​c.3908A>G​(p.Gln1303Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,461,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: NOS1 NM_000620.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.47
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28816056).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOS1	NM_000620.5	c.3908A>G	p.Gln1303Arg	missense_variant	Exon 26 of 29	ENST00000317775.11	NP_000611.1
NOS1	NM_001204218.2	c.4010A>G	p.Gln1337Arg	missense_variant	Exon 27 of 30		NP_001191147.1
NOS1	NM_001204213.2	c.2900A>G	p.Gln967Arg	missense_variant	Exon 25 of 28		NP_001191142.1
NOS1	NM_001204214.2	c.2900A>G	p.Gln967Arg	missense_variant	Exon 25 of 28		NP_001191143.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOS1	ENST00000317775.11	c.3908A>G	p.Gln1303Arg	missense_variant	Exon 26 of 29	1	NM_000620.5	ENSP00000320758.6
NOS1	ENST00000338101.8	c.4010A>G	p.Gln1337Arg	missense_variant	Exon 26 of 29	5		ENSP00000337459.4
NOS1	ENST00000618760.4	c.4010A>G	p.Gln1337Arg	missense_variant	Exon 27 of 30	5		ENSP00000477999.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000342 AC: 5 AN: 1461870 Hom.: 0 Cov.: 32 AF XY: 0.00000550 AC XY: 4 AN XY: 727236

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111998

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 06, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4010A>G (p.Q1337R) alteration is located in exon 27 (coding exon 26) of the NOS1 gene. This alteration results from a A to G substitution at nucleotide position 4010, causing the glutamine (Q) at amino acid position 1337 to be replaced by an arginine (R). 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	0.10
BayesDel_addAF	Benign	0.0018	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	D;.;.;D
Eigen	Benign	-0.11
Eigen_PC	Benign	0.038
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.83	T;T;.;T
M_CAP	Benign	0.054	D
MetaRNN	Benign	0.29	T;T;T;T
MetaSVM	Benign	-0.32	T
MutationAssessor	Benign	0.15	N;.;.;.
PhyloP100		3.5
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-2.3	N;.;N;.
REVEL	Benign	0.27
Sift	Benign	0.096	T;.;D;.
Sift4G	Benign	0.10	T;T;T;T
Polyphen		0.015	B;.;.;.
Vest4		0.33
MutPred		0.42		Gain of MoRF binding (P = 0.0165);.;.;.;
MVP		0.83
MPC		0.62
ClinPred		0.53	D
GERP RS		4.0
Varity_R		0.15
gMVP		0.73
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

hg19: chr12-117660587;