7-151013819-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000603.5(NOS3):c.3351T>C(p.Val1117=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00931 in 1,609,760 control chromosomes in the GnomAD database, including 938 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.045 (495 hom., cov: 33)
  • Exomes 𝑓: 0.0056 (443 hom.)
• Consequence: NOS3 NM_000603.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.14

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

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 7-151013819-T-C is Benign according to our data. Variant chr7-151013819-T-C is described in ClinVar as [Benign]. Clinvar id is 403252.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.14 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.149 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOS3	NM_000603.5	c.3351T>C	p.Val1117=	synonymous_variant	26/27	ENST00000297494.8
ATG9B	NR_073169.1	n.2551A>G		non_coding_transcript_exon_variant	17/18
ATG9B	NR_133652.1	n.3288A>G		non_coding_transcript_exon_variant	16/17
ATG9B	XR_007060009.1	n.3331A>G		non_coding_transcript_exon_variant	14/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOS3	ENST00000297494.8	c.3351T>C	p.Val1117=	synonymous_variant	26/27	1	NM_000603.5	P1

Frequencies

GnomAD3 genomes AF: 0.0444 AC: 6763 AN: 152182 Hom.: 491 Cov.: 33

Gnomad AFR AF: 0.152

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0175

Gnomad ASJ AF: 0.00605

Gnomad EAS AF: 0.00462

Gnomad SAS AF: 0.00827

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.000926

Gnomad OTH AF: 0.0316

GnomAD3 exomes AF: 0.0137 AC: 3273 AN: 239072 Hom.: 201 AF XY: 0.0108 AC XY: 1406 AN XY: 129888

Gnomad AFR exome AF: 0.157

Gnomad AMR exome AF: 0.00970

Gnomad ASJ exome AF: 0.00677

Gnomad EAS exome AF: 0.00614

Gnomad SAS exome AF: 0.00831

Gnomad FIN exome AF: 0.0000501

Gnomad NFE exome AF: 0.00117

Gnomad OTH exome AF: 0.00773

GnomAD4 exome AF: 0.00562 AC: 8195 AN: 1457460 Hom.: 443 Cov.: 35 AF XY: 0.00527 AC XY: 3816 AN XY: 724776

Gnomad4 AFR exome AF: 0.159

Gnomad4 AMR exome AF: 0.0108

Gnomad4 ASJ exome AF: 0.00643

Gnomad4 EAS exome AF: 0.00324

Gnomad4 SAS exome AF: 0.00788

Gnomad4 FIN exome AF: 0.0000191

Gnomad4 NFE exome AF: 0.000509

Gnomad4 OTH exome AF: 0.0120

GnomAD4 genome AF: 0.0446 AC: 6794 AN: 152300 Hom.: 495 Cov.: 33 AF XY: 0.0432 AC XY: 3214 AN XY: 74474

Gnomad4 AFR AF: 0.152

Gnomad4 AMR AF: 0.0174

Gnomad4 ASJ AF: 0.00605

Gnomad4 EAS AF: 0.00463

Gnomad4 SAS AF: 0.00849

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000926

Gnomad4 OTH AF: 0.0313

Alfa AF: 0.0165 Hom.: 201

Bravo AF: 0.0516

Asia WGS AF: 0.0240 AC: 85 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 04, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
Cadd	Benign	13
Dann	Benign	0.88

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: rs3918211; hg19: chr7-150710907;