7-150996468-G-C

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_000603.5(NOS3):​c.335G>C​(p.Arg112Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000119 in 1,590,188 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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: 𝑓 0.000021 (0 hom., cov: 26)
  • Exomes 𝑓: 0.000011 (0 hom.)
• 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: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.015100747).
• BS2: High AC in GnomAdExome4 at 16 AD gene.

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.335G>C	p.Arg112Pro	missense	Exon 4 of 27	NP_000594.2
	NOS3	NM_001160111.1		c.335G>C	p.Arg112Pro	missense	Exon 3 of 14	NP_001153583.1	P29474-2
	NOS3	NM_001160110.1		c.335G>C	p.Arg112Pro	missense	Exon 3 of 14	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.335G>C	p.Arg112Pro	missense	Exon 4 of 27	ENSP00000297494.3	P29474-1
	NOS3	ENST00000484524.5	TSL:1	c.335G>C	p.Arg112Pro	missense	Exon 3 of 14	ENSP00000420215.1	P29474-2
	NOS3	ENST00000467517.1	TSL:1	c.335G>C	p.Arg112Pro	missense	Exon 3 of 14	ENSP00000420551.1	P29474-3

Frequencies

GnomAD3 genomes AF: 0.0000206 AC: 3 AN: 145944 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000205

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000877 AC: 19 AN: 216676 AF XY: 0.0000592

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000597

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.0000111 AC: 16 AN: 1444138 Hom.: 0 Cov.: 34 AF XY: 0.00000837 AC XY: 6 AN XY: 716682

African (AFR) AF: 0.00 AC: 0 AN: 33174

American (AMR) AF: 0.000377 AC: 16 AN: 42408

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25726

East Asian (EAS) AF: 0.00 AC: 0 AN: 39120

South Asian (SAS) AF: 0.00 AC: 0 AN: 83960

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50640

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5740

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1103632

Other (OTH) AF: 0.00 AC: 0 AN: 59738

GnomAD4 genome AF: 0.0000205 AC: 3 AN: 146050 Hom.: 0 Cov.: 26 AF XY: 0.0000141 AC XY: 1 AN XY: 70906

African (AFR) AF: 0.00 AC: 0 AN: 38996

American (AMR) AF: 0.000205 AC: 3 AN: 14630

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3428

East Asian (EAS) AF: 0.00 AC: 0 AN: 4816

South Asian (SAS) AF: 0.00 AC: 0 AN: 4432

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10002

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66566

Other (OTH) AF: 0.00 AC: 0 AN: 2006

Alfa AF: 0.00 Hom.: 27

ExAC AF: 0.0000919 AC: 11

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	17
DANN	Benign	0.97
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.68
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.30	N
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.0044	T
MetaRNN	Benign	0.015	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L
PhyloP100		0.28
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.22
Sift	Benign	0.28	T
Sift4G	Benign	0.28	T
Polyphen		0.0070	B
Vest4		0.19
MutPred		0.32		Gain of glycosylation at R112 (P = 0.0038)
MVP		0.53
MPC		0.091
ClinPred		0.047	T
GERP RS		3.9
Varity_R		0.32
gMVP		0.67
Mutation Taster		=73/27	polymorphism

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: rs3918166; hg19: chr7-150693556;