NM_000603.5:c.3256-12G>A

Variant names:

• chr7-151013712-G-A
• rs77325852
• NM_000603.5:c.3256-12G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000603.5(NOS3):​c.3256-12G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0143 in 1,157,552 control chromosomes in the GnomAD database, including 1,400 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.054 (738 hom., cov: 33)
  • Exomes 𝑓: 0.0083 (662 hom.)
• Consequence: NOS3 NM_000603.5 intron
• Scores: Splicing: ADA: 0.00005298
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.327
• Publications: 2 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 7-151013712-G-A is Benign according to our data. Variant chr7-151013712-G-A is described in ClinVar as Benign. ClinVar VariationId is 1279688.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.182 is higher than 0.05.

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.3256-12G>A		intron	N/A	NP_000594.2
	ATG9B	NR_073169.1		n.2640+18C>T		intron	N/A
	ATG9B	NR_133652.1		n.3377+18C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOS3	ENST00000297494.8	TSL:1 MANE Select	c.3256-12G>A		intron	N/A	ENSP00000297494.3	P29474-1
	ATG9B	ENST00000605952.5	TSL:1	n.*526+18C>T		intron	N/A	ENSP00000475737.2	Q674R7-1
	ATG9B	ENST00000617967.4	TSL:1	n.2606+18C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0540 AC: 8124 AN: 150354 Hom.: 738 Cov.: 33

Gnomad AFR AF: 0.185

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0185

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000391

Gnomad SAS AF: 0.00125

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0390

Gnomad NFE AF: 0.00117

Gnomad OTH AF: 0.0424

GnomAD2 exomes AF: 0.0139 AC: 2662 AN: 191984 AF XY: 0.0101

Gnomad AFR exome AF: 0.197

Gnomad AMR exome AF: 0.0103

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00117

Gnomad OTH exome AF: 0.00780

GnomAD4 exome AF: 0.00832 AC: 8379 AN: 1007082 Hom.: 662 Cov.: 31 AF XY: 0.00711 AC XY: 3608 AN XY: 507716

African (AFR) AF: 0.232 AC: 6399 AN: 27610

American (AMR) AF: 0.0125 AC: 438 AN: 35112

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20782

East Asian (EAS) AF: 0.0000957 AC: 3 AN: 31360

South Asian (SAS) AF: 0.000535 AC: 39 AN: 72846

European-Finnish (FIN) AF: 0.0000251 AC: 1 AN: 39870

Middle Eastern (MID) AF: 0.0178 AC: 76 AN: 4268

European-Non Finnish (NFE) AF: 0.000968 AC: 708 AN: 731446

Other (OTH) AF: 0.0163 AC: 715 AN: 43788

GnomAD4 genome AF: 0.0540 AC: 8131 AN: 150470 Hom.: 738 Cov.: 33 AF XY: 0.0521 AC XY: 3830 AN XY: 73540

African (AFR) AF: 0.185 AC: 7666 AN: 41410

American (AMR) AF: 0.0184 AC: 280 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3422

East Asian (EAS) AF: 0.000392 AC: 2 AN: 5102

South Asian (SAS) AF: 0.000835 AC: 4 AN: 4788

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9958

Middle Eastern (MID) AF: 0.0420 AC: 12 AN: 286

European-Non Finnish (NFE) AF: 0.00117 AC: 79 AN: 67268

Other (OTH) AF: 0.0420 AC: 88 AN: 2096

Alfa AF: 0.0205 Hom.: 49

Bravo AF: 0.0612

Asia WGS AF: 0.0110 AC: 38 AN: 3474

ClinVar

ClinVar submissions

Significance: 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	-0.79
CADD	Benign	6.1
DANN	Benign	0.93
PhyloP100		-0.33
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000053
dbscSNV1_RF	Benign	0.0
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: rs77325852; hg19: chr7-150710800;