NM_000603.5:c.3324G>C

Variant names:

• chr7-151013792-G-C
• rs144040397
• NM_000603.5:c.3324G>C

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_000603.5(NOS3):​c.3324G>C​(p.Arg1108Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00171 in 1,611,238 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0019 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0017 (20 hom.)
• Consequence: NOS3 NM_000603.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.555
• Publications: 1 publications found

Genes affected

NOS3 (HGNC:7876): (nitric oxide synthase 3) Nitric oxide is a reactive free radical which acts as a biologic mediator in several processes, including neurotransmission and antimicrobial and antitumoral activities. Nitric oxide is synthesized from L-arginine by nitric oxide synthases. Variations in this gene are associated with susceptibility to coronary spasm. Alternative splicing and the use of alternative promoters results in multiple transcript variants. [provided by RefSeq, Oct 2016]

ATG9B (HGNC:21899): (autophagy related 9B) This gene functions in the regulation of autophagy, a lysosomal degradation pathway. This gene also functions as an antisense transcript in the posttranscriptional regulation of the endothelial nitric oxide synthase 3 gene, which has 3' overlap with this gene on the opposite strand. Mutations in this gene and disruption of the autophagy process have been associated with multiple cancers. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2012]

ACMG classification

Our verdict: Benign. The variant received -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant 7-151013792-G-C is Benign according to our data. Variant chr7-151013792-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 709432.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.555 with no splicing effect.
• BS2: High AC in GnomAd4 at 282 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000603.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOS3	NM_000603.5	MANE Select	c.3324G>C	p.Arg1108Arg	synonymous	Exon 26 of 27	NP_000594.2
	ATG9B	NR_073169.1		n.2578C>G		non_coding_transcript_exon	Exon 17 of 18
	ATG9B	NR_133652.1		n.3315C>G		non_coding_transcript_exon	Exon 16 of 17

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOS3	ENST00000297494.8	TSL:1 MANE Select	c.3324G>C	p.Arg1108Arg	synonymous	Exon 26 of 27	ENSP00000297494.3	P29474-1
	ATG9B	ENST00000605952.5	TSL:1	n.*464C>G		non_coding_transcript_exon	Exon 16 of 17	ENSP00000475737.2	Q674R7-1
	ATG9B	ENST00000617967.4	TSL:1	n.2544C>G		non_coding_transcript_exon	Exon 17 of 18

Frequencies

GnomAD3 genomes AF: 0.00185 AC: 282 AN: 152228 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00150

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00150

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00414

Gnomad FIN AF: 0.00217

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00206

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00198 AC: 479 AN: 242098 AF XY: 0.00215

Gnomad AFR exome AF: 0.00209

Gnomad AMR exome AF: 0.000882

Gnomad ASJ exome AF: 0.00284

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00149

Gnomad NFE exome AF: 0.00185

Gnomad OTH exome AF: 0.00153

GnomAD4 exome AF: 0.00170 AC: 2481 AN: 1458892 Hom.: 20 Cov.: 35 AF XY: 0.00179 AC XY: 1298 AN XY: 725636

African (AFR) AF: 0.00197 AC: 66 AN: 33446

American (AMR) AF: 0.00112 AC: 50 AN: 44466

Ashkenazi Jewish (ASJ) AF: 0.00277 AC: 72 AN: 26028

East Asian (EAS) AF: 0.00 AC: 0 AN: 39560

South Asian (SAS) AF: 0.00481 AC: 413 AN: 85806

European-Finnish (FIN) AF: 0.00126 AC: 66 AN: 52378

Middle Eastern (MID) AF: 0.00347 AC: 20 AN: 5760

European-Non Finnish (NFE) AF: 0.00154 AC: 1711 AN: 1111206

Other (OTH) AF: 0.00138 AC: 83 AN: 60242

GnomAD4 genome AF: 0.00185 AC: 282 AN: 152346 Hom.: 0 Cov.: 33 AF XY: 0.00187 AC XY: 139 AN XY: 74492

African (AFR) AF: 0.00149 AC: 62 AN: 41584

American (AMR) AF: 0.00150 AC: 23 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00414 AC: 20 AN: 4826

European-Finnish (FIN) AF: 0.00217 AC: 23 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00206 AC: 140 AN: 68028

Other (OTH) AF: 0.00236 AC: 5 AN: 2116

Alfa AF: 0.00187 Hom.: 0

Bravo AF: 0.00147

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	8.2
DANN	Benign	0.82
PhyloP100		-0.56
Mutation Taster		=99/1	polymorphism

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: rs144040397; hg19: chr7-150710880;