dbSNP rs746179519: NOS3:c.271-7G>A (chr7-150996397-G-A) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_000603.5(NOS3):c.271-7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000285 in 1,226,748 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000042 ( 0 hom., cov: 11)

Exomes 𝑓: 0.000028 ( 0 hom. )

Consequence

NOS3
NM_000603.5 splice_region, intron

Scores

Splicing: ADA: 0.0001051

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.271

Variant links:

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]

NOS3 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BS2

High AC in GnomAdExome4 at 32 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
NOS3	NM_000603.5 link	c.271-7G>A	splice_region_variant, intron_variant	Intron 3 of 26	ENST00000297494.8	NP_000594.2	P29474-1
NOS3	NM_001160111.1 link	c.271-7G>A	splice_region_variant, intron_variant	Intron 2 of 13		NP_001153583.1	P29474-2
NOS3	NM_001160110.1 link	c.271-7G>A	splice_region_variant, intron_variant	Intron 2 of 13		NP_001153582.1	P29474-3
NOS3	NM_001160109.2 link	c.271-7G>A	splice_region_variant, intron_variant	Intron 2 of 13		NP_001153581.1	P29474A0S0A6

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
NOS3	ENST00000297494.8 link	c.271-7G>A	splice_region_variant, intron_variant	Intron 3 of 26	1	NM_000603.5	ENSP00000297494.3	P29474-1
NOS3	ENST00000484524.5 link	c.271-7G>A	splice_region_variant, intron_variant	Intron 2 of 13	1		ENSP00000420215.1	P29474-2
NOS3	ENST00000467517.1 link	c.271-7G>A	splice_region_variant, intron_variant	Intron 2 of 13	1		ENSP00000420551.1	P29474-3
NOS3	ENST00000461406.5 link	c.-37+1083G>A	intron_variant	Intron 2 of 23	2		ENSP00000417143.1	E7ESA7

Frequencies

GnomAD3 genomes

AF:

0.0000424

AC:

AN:

70706

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000204

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000350

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000260

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000264

AC:

AN:

151456

Hom.:

AF XY:

0.0000247

AC XY:

AN XY:

80896

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000881

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.000230

GnomAD4 exome

AF:

0.0000277

AC:

AN:

1156042

Hom.:

Cov.:

AF XY:

0.0000370

AC XY:

AN XY:

567206

show subpopulations

Gnomad4 AFR exome

AF:

0.0000406

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000753

Gnomad4 SAS exome

AF:

0.0000782

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000238

Gnomad4 OTH exome

AF:

0.0000478

GnomAD4 genome

AF:

0.0000424

AC:

AN:

70706

Hom.:

Cov.:

AF XY:

0.0000315

AC XY:

AN XY:

31750

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000204

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000350

Gnomad4 NFE

AF:

0.0000260

Gnomad4 OTH

AF:

0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

0.53

DANN

Benign

0.63

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00011

dbscSNV1_RF

Benign

0.0

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over