rs760406810

Variant names:

• chr19-49556400-C-A
• rs760406810
• NM_001270960.2:c.751G>T

Your query was ambiguous. Multiple possible variants found:

• chr19-49556400-C-A
• chr19-49556400-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001270960.2(NOSIP):​c.751G>T​(p.Val251Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000658 in 152,030 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. V251M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NOSIP NM_001270960.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.44
• Publications: 3 publications found

Genes affected

NOSIP (HGNC:17946): (nitric oxide synthase interacting protein) The protein encoded by this gene may modulate the activity and localization of nitric oxide synthase (endothelial and neuronal) and thus nitric oxide production. Alternative splicing results in multiple transcript variants that encode the same protein. [provided by RefSeq, Aug 2012]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.786

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001270960.2. 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
	NOSIP	NM_001270960.2	MANE Select	c.751G>T	p.Val251Leu	missense	Exon 8 of 9	NP_001257889.1	Q9Y314
	NOSIP	NM_001363649.3		c.760G>T	p.Val254Leu	missense	Exon 9 of 10	NP_001350578.1	A0A075B6F9
	NOSIP	NM_001439222.1		c.760G>T	p.Val254Leu	missense	Exon 8 of 9	NP_001426151.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NOSIP	ENST00000596358.6	TSL:1 MANE Select	c.751G>T	p.Val251Leu	missense	Exon 8 of 9	ENSP00000470034.1	Q9Y314
	NOSIP	ENST00000874168.1		c.778G>T	p.Val260Leu	missense	Exon 8 of 9	ENSP00000544227.1
	NOSIP	ENST00000339093.7	TSL:5	c.760G>T	p.Val254Leu	missense	Exon 8 of 9	ENSP00000343497.3	A0A075B6F9

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152030 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250688 AF XY: 0.00000737

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 FIN exome AF: 0.0000465

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1461586 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727118

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53286

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111928

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152030 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74260

African (AFR) AF: 0.00 AC: 0 AN: 41366

American (AMR) AF: 0.00 AC: 0 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67988

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.12	T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.28	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Uncertain	0.13	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		5.4
PrimateAI	Pathogenic	0.81	D
REVEL	Pathogenic	0.67
Sift4G	Benign	0.083	T
Polyphen		0.96	D
Vest4		0.63
MutPred		0.63		Gain of catalytic residue at V251 (P = 0.0064)
MVP		0.85
ClinPred		0.89	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.47
gMVP		0.89
Mutation Taster		=44/56	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs760406810; hg19: chr19-50059657;