7-151010256-G-T

Position:

• chr7-151010256-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000297494.8(NOS3):​c.2654G>T​(p.Arg885Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00211 in 1,613,000 control chromosomes in the GnomAD database, including 55 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.010 (34 hom., cov: 34)
  • Exomes 𝑓: 0.0013 (21 hom.)
• Consequence: NOS3 ENST00000297494.8 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.02

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003750503).
• BP6: Variant 7-151010256-G-T is Benign according to our data. Variant chr7-151010256-G-T is described in ClinVar as [Benign]. Clinvar id is 792094.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0102 (1548/152362) while in subpopulation AFR AF= 0.035 (1456/41578). AF 95% confidence interval is 0.0335. There are 34 homozygotes in gnomad4. There are 740 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1548 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NOS3	NM_000603.5	c.2654G>T	p.Arg885Met	missense_variant	21/27	ENST00000297494.8	NP_000594.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NOS3	ENST00000297494.8	c.2654G>T	p.Arg885Met	missense_variant	21/27	1	NM_000603.5	ENSP00000297494	P1
NOS3	ENST00000461406.5	c.2036G>T	p.Arg679Met	missense_variant	18/24	2		ENSP00000417143
NOS3	ENST00000475017.1	c.536G>T	p.Arg179Met	missense_variant	4/7	2		ENSP00000418245

Frequencies

GnomAD3 genomes AF: 0.0101 AC: 1537 AN: 152244 Hom.: 33 Cov.: 34

Gnomad AFR AF: 0.0349

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00301

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00716

GnomAD3 exomes AF: 0.00296 AC: 739 AN: 249946 Hom.: 13 AF XY: 0.00228 AC XY: 308 AN XY: 135352

Gnomad AFR exome AF: 0.0359

Gnomad AMR exome AF: 0.00191

Gnomad ASJ exome AF: 0.00360

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000262

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.000346

Gnomad OTH exome AF: 0.00197

GnomAD4 exome AF: 0.00127 AC: 1851 AN: 1460638 Hom.: 21 Cov.: 32 AF XY: 0.00112 AC XY: 814 AN XY: 726652

Gnomad4 AFR exome AF: 0.0374

Gnomad4 AMR exome AF: 0.00190

Gnomad4 ASJ exome AF: 0.00283

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000162

Gnomad4 FIN exome AF: 0.0000188

Gnomad4 NFE exome AF: 0.000181

Gnomad4 OTH exome AF: 0.00320

GnomAD4 genome AF: 0.0102 AC: 1548 AN: 152362 Hom.: 34 Cov.: 34 AF XY: 0.00993 AC XY: 740 AN XY: 74500

Gnomad4 AFR AF: 0.0350

Gnomad4 AMR AF: 0.00300

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.00709

Alfa AF: 0.00257 Hom.: 8

Bravo AF: 0.0120

ESP6500AA AF: 0.0345 AC: 152

ESP6500EA AF: 0.000465 AC: 4

ExAC AF: 0.00361 AC: 438

Asia WGS AF: 0.00404 AC: 14 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000415

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	24
DANN	Benign	0.94
DEOGEN2	Benign	0.25	T;T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.43	T;T
MetaRNN	Benign	0.0038	T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.2	L;.
MutationTaster	Benign	0.61	D;N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.6	N;N
REVEL	Benign	0.10
Sift	Benign	0.12	T;T
Sift4G	Benign	0.14	T;T
Polyphen		0.0020	B;B
Vest4		0.22
MVP		0.74
MPC		0.74
ClinPred		0.048	T
GERP RS		4.4
Varity_R		0.077
gMVP		0.34

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.20		Position offset: -44

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs3918201; hg19: chr7-150707344;