12-117218048-A-C

Variant names:

• chr12-117218048-A-C
• NM_000620.5:c.4287T>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000620.5(NOS1):​c.4287T>G​(p.Asp1429Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,712 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: NOS1 NM_000620.5 missense, splice_region
• Scores: Splicing: ADA: 0.00006726
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.289

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOS1	NM_000620.5	c.4287T>G	p.Asp1429Glu	missense_variant, splice_region_variant	Exon 28 of 29	ENST00000317775.11	NP_000611.1
NOS1	NM_001204218.2	c.4389T>G	p.Asp1463Glu	missense_variant, splice_region_variant	Exon 29 of 30		NP_001191147.1
NOS1	NM_001204213.2	c.3279T>G	p.Asp1093Glu	missense_variant, splice_region_variant	Exon 27 of 28		NP_001191142.1
NOS1	NM_001204214.2	c.3279T>G	p.Asp1093Glu	missense_variant, splice_region_variant	Exon 27 of 28		NP_001191143.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOS1	ENST00000317775.11	c.4287T>G	p.Asp1429Glu	missense_variant, splice_region_variant	Exon 28 of 29	1	NM_000620.5	ENSP00000320758.6
NOS1	ENST00000338101.8	c.4389T>G	p.Asp1463Glu	missense_variant, splice_region_variant	Exon 28 of 29	5		ENSP00000337459.4
NOS1	ENST00000618760.4	c.4389T>G	p.Asp1463Glu	missense_variant, splice_region_variant	Exon 29 of 30	5		ENSP00000477999.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457712 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 725486

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: 9.02e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	13
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.43	T;.;.;T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.50
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.87	D;D;.;D
M_CAP	Benign	0.048	D
MetaRNN	Uncertain	0.68	D;D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	M;.;.;.
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.1	N;.;N;.
REVEL	Benign	0.19
Sift	Uncertain	0.0040	D;.;D;.
Sift4G	Uncertain	0.021	D;D;D;D
Polyphen		0.95	P;.;.;.
Vest4		0.56
MutPred		0.35		Gain of sheet (P = 0.0016);.;.;.;
MVP		0.60
MPC		1.1
ClinPred		0.96	D
GERP RS		-3.6
Varity_R		0.21
gMVP		0.70

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000067
dbscSNV1_RF	Benign	0.16
SpliceAI score (max)		0.29		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.29		Position offset: -23

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: chr12-117655853;