12-117220167-C-A

Variant names:

• chr12-117220167-C-A
• rs761925815
• NM_000620.5:c.4078G>T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP3 BS2

The NM_000620.5(NOS1):​c.4078G>T​(p.Ala1360Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,613,898 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: NOS1 NM_000620.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.89

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 -3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.827
• BS2: High AC in GnomAd4 at 15 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOS1	NM_000620.5	c.4078G>T	p.Ala1360Ser	missense_variant	Exon 27 of 29	ENST00000317775.11	NP_000611.1
NOS1	NM_001204218.2	c.4180G>T	p.Ala1394Ser	missense_variant	Exon 28 of 30		NP_001191147.1
NOS1	NM_001204213.2	c.3070G>T	p.Ala1024Ser	missense_variant	Exon 26 of 28		NP_001191142.1
NOS1	NM_001204214.2	c.3070G>T	p.Ala1024Ser	missense_variant	Exon 26 of 28		NP_001191143.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOS1	ENST00000317775.11	c.4078G>T	p.Ala1360Ser	missense_variant	Exon 27 of 29	1	NM_000620.5	ENSP00000320758.6
NOS1	ENST00000338101.8	c.4180G>T	p.Ala1394Ser	missense_variant	Exon 27 of 29	5		ENSP00000337459.4
NOS1	ENST00000618760.4	c.4180G>T	p.Ala1394Ser	missense_variant	Exon 28 of 30	5		ENSP00000477999.1

Frequencies

GnomAD3 genomes AF: 0.0000985 AC: 15 AN: 152214 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000160 AC: 4 AN: 249526 Hom.: 0 AF XY: 0.0000148 AC XY: 2 AN XY: 135230

Gnomad AFR exome AF: 0.000255

Gnomad AMR exome AF: 0.00

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: 0.00

GnomAD4 exome AF: 0.0000109 AC: 16 AN: 1461684 Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7 AN XY: 727158

Gnomad4 AFR exome AF: 0.000448

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: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000985 AC: 15 AN: 152214 Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5 AN XY: 74356

Gnomad4 AFR AF: 0.000362

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000989 Hom.: 0

Bravo AF: 0.000117

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 12, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.4180G>T (p.A1394S) alteration is located in exon 28 (coding exon 27) of the NOS1 gene. This alteration results from a G to T substitution at nucleotide position 4180, causing the alanine (A) at amino acid position 1394 to be replaced by a serine (S). 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	Uncertain	0.48
BayesDel_addAF	Uncertain	0.027	T
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	D;.;.;D
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D;D;.;D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.83	D;D;D;D
MetaSVM	Uncertain	0.73	D
MutationAssessor	Uncertain	2.3	M;.;.;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-2.6	D;.;D;.
REVEL	Pathogenic	0.67
Sift	Uncertain	0.013	D;.;D;.
Sift4G	Uncertain	0.032	D;D;D;D
Polyphen		1.0	D;.;.;.
Vest4		0.73
MVP		0.85
MPC		1.4
ClinPred		0.76	D
GERP RS		4.4
Varity_R		0.42
gMVP		0.78

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

Publications

LitVar

Other links and lift over

dbSNP: rs761925815; hg19: chr12-117657972;