19-49557095-C-A

Variant names:

• chr19-49557095-C-A
• rs2080262026
• NM_001270960.2:c.413G>T

Variant summary

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

The NM_001270960.2(NOSIP):​c.413G>T​(p.Ser138Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,458,848 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: NOSIP NM_001270960.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.554

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

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=0.09845421).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOSIP	NM_001270960.2	c.413G>T	p.Ser138Ile	missense_variant	Exon 5 of 9	ENST00000596358.6	NP_001257889.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOSIP	ENST00000596358.6	c.413G>T	p.Ser138Ile	missense_variant	Exon 5 of 9	1	NM_001270960.2	ENSP00000470034.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1458848 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 725450

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000498

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 26, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.413G>T (p.S138I) alteration is located in exon 6 (coding exon 4) of the NOSIP gene. This alteration results from a G to T substitution at nucleotide position 413, causing the serine (S) at amino acid position 138 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	14
DANN	Benign	0.81
DEOGEN2	Benign	0.093	T;T;T;.
Eigen	Benign	-0.87
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.24	T;T;T;T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.098	T;T;T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	1.9	.;L;.;.
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-2.3	N;.;.;.
REVEL	Benign	0.073
Sift	Benign	0.29	T;.;.;.
Sift4G	Benign	0.13	T;T;.;.
Polyphen		0.023	.;B;.;.
Vest4		0.21
MutPred		0.21		Loss of phosphorylation at S138 (P = 0.0219);Loss of phosphorylation at S138 (P = 0.0219);Loss of phosphorylation at S138 (P = 0.0219);Loss of phosphorylation at S138 (P = 0.0219);
MVP		0.63
ClinPred		0.069	T
GERP RS		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.045
gMVP		0.44

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

Publications

LitVar

Other links and lift over

dbSNP: rs2080262026; hg19: chr19-50060352;