19-49557132-G-T

Variant names:

• chr19-49557132-G-T
• rs375469093
• NM_001270960.2:c.376C>A

Variant summary

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

The NM_001270960.2(NOSIP):​c.376C>A​(p.Leu126Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000682 in 1,612,748 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: NOSIP NM_001270960.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.49
• Publications: 0 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2274139).

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.376C>A	p.Leu126Ile	missense	Exon 5 of 9	NP_001257889.1	Q9Y314
	NOSIP	NM_001363649.3		c.376C>A	p.Leu126Ile	missense	Exon 6 of 10	NP_001350578.1	A0A075B6F9
	NOSIP	NM_001439222.1		c.376C>A	p.Leu126Ile	missense	Exon 5 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.376C>A	p.Leu126Ile	missense	Exon 5 of 9	ENSP00000470034.1	Q9Y314
	NOSIP	ENST00000874168.1		c.376C>A	p.Leu126Ile	missense	Exon 5 of 9	ENSP00000544227.1
	NOSIP	ENST00000339093.7	TSL:5	c.376C>A	p.Leu126Ile	missense	Exon 5 of 9	ENSP00000343497.3	A0A075B6F9

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152246 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000964

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1460502 Hom.: 0 Cov.: 33 AF XY: 0.00000688 AC XY: 5 AN XY: 726450

African (AFR) AF: 0.000179 AC: 6 AN: 33458

American (AMR) AF: 0.00 AC: 0 AN: 44558

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26068

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.00 AC: 0 AN: 85948

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53178

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111578

Other (OTH) AF: 0.0000166 AC: 1 AN: 60294

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152246 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74374

African (AFR) AF: 0.0000964 AC: 4 AN: 41474

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68046

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.0000331 Hom.: 0

Bravo AF: 0.0000302

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.068	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	20
DANN	Benign	0.83
DEOGEN2	Benign	0.048	T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.043
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.076	D
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	-0.29	N
PhyloP100		5.5
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-0.51	N
REVEL	Uncertain	0.35
Sift	Benign	0.43	T
Sift4G	Benign	0.60	T
Polyphen		0.17	B
Vest4		0.28
MVP		0.73
ClinPred		0.72	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
gMVP		0.26
Mutation Taster		=73/27	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs375469093; hg19: chr19-50060389;