12-117222782-T-C

Position:

• chr12-117222782-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PM2 PP2 BP4 BS2

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. 14/21 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

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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, NOS1
• BP4: Computational evidence support a benign effect (MetaRNN=0.28816056).
• BS2: High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOS1	NM_000620.5	c.3908A>G	p.Gln1303Arg	missense_variant	26/29	ENST00000317775.11
NOS1	NM_001204218.2	c.4010A>G	p.Gln1337Arg	missense_variant	27/30
NOS1	NM_001204213.2	c.2900A>G	p.Gln967Arg	missense_variant	25/28
NOS1	NM_001204214.2	c.2900A>G	p.Gln967Arg	missense_variant	25/28

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOS1	ENST00000317775.11	c.3908A>G	p.Gln1303Arg	missense_variant	26/29	1	NM_000620.5	P1
NOS1	ENST00000338101.8	c.4010A>G	p.Gln1337Arg	missense_variant	26/29	5
NOS1	ENST00000618760.4	c.4010A>G	p.Gln1337Arg	missense_variant	27/30	5

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 06, 2022

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;.;.;.
MutationTaster	Benign	0.97	D;D;D
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

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-117660587;