7-150996468-G-T

Variant names:

• chr7-150996468-G-T
• rs3918166
• NM_000603.5:c.335G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000603.5(NOS3):​c.335G>T​(p.Arg112Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 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. R112Q) has been classified as Benign.

• Frequency: Genomes: not found (cov: 26)
• Consequence: NOS3 NM_000603.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.275
• Publications: 18 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14984292).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOS3	NM_000603.5	c.335G>T	p.Arg112Leu	missense_variant	Exon 4 of 27	ENST00000297494.8	NP_000594.2
NOS3	NM_001160111.1	c.335G>T	p.Arg112Leu	missense_variant	Exon 3 of 14		NP_001153583.1
NOS3	NM_001160110.1	c.335G>T	p.Arg112Leu	missense_variant	Exon 3 of 14		NP_001153582.1
NOS3	NM_001160109.2	c.335G>T	p.Arg112Leu	missense_variant	Exon 3 of 14		NP_001153581.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOS3	ENST00000297494.8	c.335G>T	p.Arg112Leu	missense_variant	Exon 4 of 27	1	NM_000603.5	ENSP00000297494.3
NOS3	ENST00000484524.5	c.335G>T	p.Arg112Leu	missense_variant	Exon 3 of 14	1		ENSP00000420215.1
NOS3	ENST00000467517.1	c.335G>T	p.Arg112Leu	missense_variant	Exon 3 of 14	1		ENSP00000420551.1
NOS3	ENST00000461406.5	c.-37+1154G>T		intron_variant	Intron 2 of 23	2		ENSP00000417143.1

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 26

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.26	T;.;.
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.34	N
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.15	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L;L;L
PhyloP100		0.28
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-2.6	D;D;D
REVEL	Benign	0.10
Sift	Benign	0.36	T;T;T
Sift4G	Benign	0.24	T;T;T
Polyphen		0.29	B;.;.
Vest4		0.30
MutPred		0.29		Gain of glycosylation at S114 (P = 0.052);Gain of glycosylation at S114 (P = 0.052);Gain of glycosylation at S114 (P = 0.052);
MVP		0.52
MPC		0.079
ClinPred		0.15	T
GERP RS		3.9
Varity_R		0.16
gMVP		0.59
Mutation Taster		=83/17	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs3918166; hg19: chr7-150693556;