12-117223068-C-T

Variant names:

• chr12-117223068-C-T
• rs2271986
• NM_000620.5:c.3827-205G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000620.5(NOS1):​c.3827-205G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0967 in 152,186 control chromosomes in the GnomAD database, including 1,137 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.097 (1137 hom., cov: 32)
• Consequence: NOS1 NM_000620.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.352
• Publications: 11 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.272 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOS1	NM_000620.5	c.3827-205G>A		intron_variant	Intron 25 of 28	ENST00000317775.11	NP_000611.1
NOS1	NM_001204218.2	c.3929-205G>A		intron_variant	Intron 26 of 29		NP_001191147.1
NOS1	NM_001204213.2	c.2819-205G>A		intron_variant	Intron 24 of 27		NP_001191142.1
NOS1	NM_001204214.2	c.2819-205G>A		intron_variant	Intron 24 of 27		NP_001191143.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOS1	ENST00000317775.11	c.3827-205G>A		intron_variant	Intron 25 of 28	1	NM_000620.5	ENSP00000320758.6
NOS1	ENST00000338101.8	c.3929-205G>A		intron_variant	Intron 25 of 28	5		ENSP00000337459.4
NOS1	ENST00000618760.4	c.3929-205G>A		intron_variant	Intron 26 of 29	5		ENSP00000477999.1

Frequencies

GnomAD3 genomes AF: 0.0967 AC: 14703 AN: 152068 Hom.: 1129 Cov.: 32

Gnomad AFR AF: 0.0417

Gnomad AMI AF: 0.135

Gnomad AMR AF: 0.278

Gnomad ASJ AF: 0.0455

Gnomad EAS AF: 0.0225

Gnomad SAS AF: 0.0855

Gnomad FIN AF: 0.0872

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0997

Gnomad OTH AF: 0.0971

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0967 AC: 14718 AN: 152186 Hom.: 1137 Cov.: 32 AF XY: 0.0986 AC XY: 7334 AN XY: 74406

African (AFR) AF: 0.0416 AC: 1727 AN: 41536

American (AMR) AF: 0.279 AC: 4260 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.0455 AC: 158 AN: 3470

East Asian (EAS) AF: 0.0224 AC: 116 AN: 5178

South Asian (SAS) AF: 0.0848 AC: 409 AN: 4824

European-Finnish (FIN) AF: 0.0872 AC: 924 AN: 10598

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0997 AC: 6782 AN: 67996

Other (OTH) AF: 0.0975 AC: 206 AN: 2112

Alfa AF: 0.0946 Hom.: 551

Bravo AF: 0.111

Asia WGS AF: 0.0630 AC: 221 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	1.6
DANN	Benign	0.68
PhyloP100		0.35
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2271986; hg19: chr12-117660873;