rs1007311

Variant names:

• chr7-150998920-A-G
• rs1007311
• NM_000603.5:c.817-26A>G

Your query was ambiguous. Multiple possible variants found:

• chr7-150998920-A-G
• chr7-150998920-A-T

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.817-26A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.441 in 1,595,936 control chromosomes in the GnomAD database, including 158,234 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.46 (16531 hom., cov: 31)
  • Exomes 𝑓: 0.44 (141703 hom.)
• Consequence: NOS3 NM_000603.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.51
• Publications: 22 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]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 1 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 7-150998920-A-G is Benign according to our data. Variant chr7-150998920-A-G is described in ClinVar as Benign. ClinVar VariationId is 1256933.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.553 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.817-26A>G		intron	N/A	NP_000594.2
	NOS3	NM_001160111.1		c.817-26A>G		intron	N/A	NP_001153583.1	P29474-2
	NOS3	NM_001160110.1		c.817-26A>G		intron	N/A	NP_001153582.1	P29474-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOS3	ENST00000297494.8	TSL:1 MANE Select	c.817-26A>G		intron	N/A	ENSP00000297494.3	P29474-1
	NOS3	ENST00000484524.5	TSL:1	c.817-26A>G		intron	N/A	ENSP00000420215.1	P29474-2
	NOS3	ENST00000467517.1	TSL:1	c.817-26A>G		intron	N/A	ENSP00000420551.1	P29474-3

Frequencies

GnomAD3 genomes AF: 0.459 AC: 69590 AN: 151714 Hom.: 16515 Cov.: 31

Gnomad AFR AF: 0.560

Gnomad AMI AF: 0.572

Gnomad AMR AF: 0.318

Gnomad ASJ AF: 0.569

Gnomad EAS AF: 0.503

Gnomad SAS AF: 0.477

Gnomad FIN AF: 0.362

Gnomad MID AF: 0.519

Gnomad NFE AF: 0.432

Gnomad OTH AF: 0.456

GnomAD2 exomes AF: 0.431 AC: 101194 AN: 234618 AF XY: 0.438

Gnomad AFR exome AF: 0.564

Gnomad AMR exome AF: 0.248

Gnomad ASJ exome AF: 0.559

Gnomad EAS exome AF: 0.521

Gnomad FIN exome AF: 0.368

Gnomad NFE exome AF: 0.436

Gnomad OTH exome AF: 0.428

GnomAD4 exome AF: 0.440 AC: 634701 AN: 1444106 Hom.: 141703 Cov.: 43 AF XY: 0.442 AC XY: 317001 AN XY: 717558

African (AFR) AF: 0.564 AC: 18376 AN: 32604

American (AMR) AF: 0.254 AC: 10495 AN: 41262

Ashkenazi Jewish (ASJ) AF: 0.564 AC: 14277 AN: 25318

East Asian (EAS) AF: 0.490 AC: 19344 AN: 39482

South Asian (SAS) AF: 0.494 AC: 41929 AN: 84816

European-Finnish (FIN) AF: 0.380 AC: 19664 AN: 51760

Middle Eastern (MID) AF: 0.500 AC: 2590 AN: 5180

European-Non Finnish (NFE) AF: 0.435 AC: 480850 AN: 1104196

Other (OTH) AF: 0.457 AC: 27176 AN: 59488

GnomAD4 genome AF: 0.459 AC: 69631 AN: 151830 Hom.: 16531 Cov.: 31 AF XY: 0.454 AC XY: 33670 AN XY: 74184

African (AFR) AF: 0.559 AC: 23137 AN: 41378

American (AMR) AF: 0.317 AC: 4840 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.569 AC: 1975 AN: 3468

East Asian (EAS) AF: 0.503 AC: 2590 AN: 5148

South Asian (SAS) AF: 0.479 AC: 2301 AN: 4802

European-Finnish (FIN) AF: 0.362 AC: 3821 AN: 10566

Middle Eastern (MID) AF: 0.510 AC: 149 AN: 292

European-Non Finnish (NFE) AF: 0.432 AC: 29328 AN: 67878

Other (OTH) AF: 0.460 AC: 971 AN: 2110

Alfa AF: 0.462 Hom.: 3095

Bravo AF: 0.458

Asia WGS AF: 0.493 AC: 1714 AN: 3478

ClinVar

ClinVar submissions as Germline

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	-0.90
CADD	Benign	0.047
DANN	Benign	0.36
PhyloP100		-2.5
BranchPoint Hunter		1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1007311; hg19: chr7-150696008; COSMIC: COSV52491161; COSMIC: COSV52491161;