12-117227433-C-T

Variant names:

• chr12-117227433-C-T
• rs753666274
• NM_000620.5:c.3614G>A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_000620.5(NOS1):​c.3614G>A​(p.Arg1205Gln) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000328 in 1,461,574 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000033 (0 hom.)
• Consequence: NOS1 NM_000620.5 missense, splice_region
• Scores: Splicing: ADA: 0.0007619
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.13

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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08746186).
• BS2: High AC in GnomAdExome4 at 48 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOS1	NM_000620.5	c.3614G>A	p.Arg1205Gln	missense_variant, splice_region_variant	Exon 23 of 29	ENST00000317775.11	NP_000611.1
NOS1	NM_001204218.2	c.3716G>A	p.Arg1239Gln	missense_variant, splice_region_variant	Exon 24 of 30		NP_001191147.1
NOS1	NM_001204213.2	c.2606G>A	p.Arg869Gln	missense_variant, splice_region_variant	Exon 22 of 28		NP_001191142.1
NOS1	NM_001204214.2	c.2606G>A	p.Arg869Gln	missense_variant, splice_region_variant	Exon 22 of 28		NP_001191143.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOS1	ENST00000317775.11	c.3614G>A	p.Arg1205Gln	missense_variant, splice_region_variant	Exon 23 of 29	1	NM_000620.5	ENSP00000320758.6
NOS1	ENST00000338101.8	c.3716G>A	p.Arg1239Gln	missense_variant, splice_region_variant	Exon 23 of 29	5		ENSP00000337459.4
NOS1	ENST00000618760.4	c.3716G>A	p.Arg1239Gln	missense_variant, splice_region_variant	Exon 24 of 30	5		ENSP00000477999.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000563 AC: 14 AN: 248788 Hom.: 0 AF XY: 0.0000740 AC XY: 10 AN XY: 135044

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000354

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000328 AC: 48 AN: 1461574 Hom.: 0 Cov.: 32 AF XY: 0.0000413 AC XY: 30 AN XY: 727088

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: 0.000186

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000288

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000282 Hom.: 0

ExAC AF: 0.0000661 AC: 8

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 20, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3716G>A (p.R1239Q) alteration is located in exon 24 (coding exon 23) of the NOS1 gene. This alteration results from a G to A substitution at nucleotide position 3716, causing the arginine (R) at amino acid position 1239 to be replaced by a glutamine (Q). 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	0.076
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	23
DANN	Benign	0.72
DEOGEN2	Benign	0.30	T;.;.;T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.23
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.91	D;D;.;D
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.087	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.14	N;.;.;.
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.1	N;.;N;.
REVEL	Benign	0.075
Sift	Benign	0.82	T;.;T;.
Sift4G	Benign	0.79	T;T;T;T
Polyphen		0.0	B;.;.;.
Vest4		0.19
MutPred		0.56		Gain of catalytic residue at S1201 (P = 0);.;.;.;
MVP		0.30
MPC		0.64
ClinPred		0.050	T
GERP RS		4.1
Varity_R		0.11
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00076
dbscSNV1_RF	Benign	0.016
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: rs753666274; hg19: chr12-117665238;