12-117218071-C-G

Position:

• chr12-117218071-C-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 1P and 10B. PP2 BP4_Strong BP6_Moderate BS2

The NM_000620.5(NOS1):​c.4264G>C​(p.Glu1422Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000144 in 1,614,004 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00083 (1 hom., cov: 32)
  • Exomes 𝑓: 0.000072 (0 hom.)
• Consequence: NOS1 NM_000620.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 7.54

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 Benign. Variant got -9 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), NOS1. . Gene score misZ 3.6832 (greater than the threshold 3.09). Trascript score misZ 4.7179 (greater than threshold 3.09). GenCC has associacion of gene with idiopathic achalasia.
• BP4: Computational evidence support a benign effect (MetaRNN=0.032715768).
• BP6: Variant 12-117218071-C-G is Benign according to our data. Variant chr12-117218071-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 730599.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 127 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOS1	NM_000620.5	c.4264G>C	p.Glu1422Gln	missense_variant	28/29	ENST00000317775.11	NP_000611.1
NOS1	NM_001204218.2	c.4366G>C	p.Glu1456Gln	missense_variant	29/30		NP_001191147.1
NOS1	NM_001204213.2	c.3256G>C	p.Glu1086Gln	missense_variant	27/28		NP_001191142.1
NOS1	NM_001204214.2	c.3256G>C	p.Glu1086Gln	missense_variant	27/28		NP_001191143.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOS1	ENST00000317775.11	c.4264G>C	p.Glu1422Gln	missense_variant	28/29	1	NM_000620.5	ENSP00000320758.6
NOS1	ENST00000338101.8	c.4366G>C	p.Glu1456Gln	missense_variant	28/29	5		ENSP00000337459.4
NOS1	ENST00000618760.4	c.4366G>C	p.Glu1456Gln	missense_variant	29/30	5		ENSP00000477999.1

Frequencies

GnomAD3 genomes AF: 0.000835 AC: 127 AN: 152162 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00302

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: 0.000220 AC: 55 AN: 249488 Hom.: 0 AF XY: 0.000177 AC XY: 24 AN XY: 135352

Gnomad AFR exome AF: 0.00303

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000330

GnomAD4 exome AF: 0.0000718 AC: 105 AN: 1461724 Hom.: 0 Cov.: 31 AF XY: 0.0000646 AC XY: 47 AN XY: 727168

Gnomad4 AFR exome AF: 0.00257

Gnomad4 AMR exome AF: 0.000157

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: 0.00

Gnomad4 OTH exome AF: 0.000199

GnomAD4 genome AF: 0.000834 AC: 127 AN: 152280 Hom.: 1 Cov.: 32 AF XY: 0.000873 AC XY: 65 AN XY: 74452

Gnomad4 AFR AF: 0.00301

Gnomad4 AMR AF: 0.0000654

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: 0.000310 Hom.: 0

Bravo AF: 0.000850

ESP6500AA AF: 0.00225 AC: 9

ESP6500EA AF: 0.000120 AC: 1

ExAC AF: 0.000281 AC: 34

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 28, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.26
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.35	T;.;.;T
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;.;D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.033	T;T;T;T
MetaSVM	Benign	-0.89	T
MutationAssessor	Uncertain	2.6	M;.;.;.
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-1.1	N;.;N;.
REVEL	Benign	0.18
Sift	Benign	0.073	T;.;T;.
Sift4G	Benign	0.23	T;T;T;T
Polyphen		1.0	D;.;.;.
Vest4		0.67
MVP		0.63
MPC		1.4
ClinPred		0.049	T
GERP RS		4.7
Varity_R		0.25
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs201476356; hg19: chr12-117655876;