chr7-150993949-C-A

Variant names:

• chr7-150993949-C-A
• rs755710890
• NM_000603.5:c.146C>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000603.5(NOS3):​c.146C>A​(p.Ala49Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000212 in 1,414,168 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A49V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: NOS3 NM_000603.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.226

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08650851).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOS3	NM_000603.5	c.146C>A	p.Ala49Glu	missense_variant	Exon 2 of 27	ENST00000297494.8	NP_000594.2
NOS3	NM_001160111.1	c.146C>A	p.Ala49Glu	missense_variant	Exon 1 of 14		NP_001153583.1
NOS3	NM_001160110.1	c.146C>A	p.Ala49Glu	missense_variant	Exon 1 of 14		NP_001153582.1
NOS3	NM_001160109.2	c.146C>A	p.Ala49Glu	missense_variant	Exon 1 of 14		NP_001153581.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOS3	ENST00000297494.8	c.146C>A	p.Ala49Glu	missense_variant	Exon 2 of 27	1	NM_000603.5	ENSP00000297494.3
NOS3	ENST00000484524.5	c.146C>A	p.Ala49Glu	missense_variant	Exon 1 of 14	1		ENSP00000420215.1
NOS3	ENST00000467517.1	c.146C>A	p.Ala49Glu	missense_variant	Exon 1 of 14	1		ENSP00000420551.1
NOS3	ENST00000461406.5	c.-148-1254C>A		intron_variant	Intron 1 of 23	2		ENSP00000417143.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000118 AC: 2 AN: 168832 Hom.: 0 AF XY: 0.0000218 AC XY: 2 AN XY: 91690

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000373

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000802

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000212 AC: 3 AN: 1414168 Hom.: 0 Cov.: 31 AF XY: 0.00000286 AC XY: 2 AN XY: 699870

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000261

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000540

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ExAC AF: 0.00000870 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	13
DANN	Benign	0.93
DEOGEN2	Benign	0.098	T;.;.
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.81
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.54	T;T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.087	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L;L;L
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	0.30	N;N;N
REVEL	Benign	0.040
Sift	Benign	0.26	T;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0020	B;.;.
Vest4		0.27
MutPred		0.19		Gain of solvent accessibility (P = 0.0456);Gain of solvent accessibility (P = 0.0456);Gain of solvent accessibility (P = 0.0456);
MVP		0.41
MPC		0.074
ClinPred		0.081	T
GERP RS		2.9
Varity_R		0.081
gMVP		0.32

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs755710890; hg19: chr7-150691037;