19-49558953-C-T

Variant names:

• chr19-49558953-C-T
• NM_001270960.2:c.202G>A

Variant summary

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

The NM_001270960.2(NOSIP):​c.202G>A​(p.Glu68Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: NOSIP NM_001270960.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.45

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOSIP	NM_001270960.2	c.202G>A	p.Glu68Lys	missense_variant	Exon 4 of 9	ENST00000596358.6	NP_001257889.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOSIP	ENST00000596358.6	c.202G>A	p.Glu68Lys	missense_variant	Exon 4 of 9	1	NM_001270960.2	ENSP00000470034.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.202G>A (p.E68K) alteration is located in exon 5 (coding exon 3) of the NOSIP gene. This alteration results from a G to A substitution at nucleotide position 202, causing the glutamic acid (E) at amino acid position 68 to be replaced by a lysine (K). 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	Pathogenic	0.63
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T;T;T;.;.
Eigen	Benign	-0.020
Eigen_PC	Benign	0.024
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D
M_CAP	Pathogenic	0.30	D
MetaRNN	Uncertain	0.70	D;D;D;D;D
MetaSVM	Benign	-0.29	T
MutationAssessor	Pathogenic	3.0	.;M;.;.;.
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-3.3	D;.;.;.;.
REVEL	Uncertain	0.58
Sift	Uncertain	0.0050	D;.;.;.;.
Sift4G	Uncertain	0.033	D;D;.;.;.
Polyphen		0.33	.;B;.;.;.
Vest4		0.71
MutPred		0.66		Gain of methylation at E68 (P = 0.016);Gain of methylation at E68 (P = 0.016);Gain of methylation at E68 (P = 0.016);Gain of methylation at E68 (P = 0.016);Gain of methylation at E68 (P = 0.016);
MVP		0.76
ClinPred		0.99	D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.40
gMVP		0.65

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-50062210;