19-49556714-A-T

Variant names:

• chr19-49556714-A-T
• rs141077974
• NM_001270960.2:c.560T>A

Variant summary

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

The NM_001270960.2(NOSIP):​c.560T>A​(p.Met187Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,456,260 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. M187T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NOSIP NM_001270960.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.65
• 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 2 ACMG points.

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

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.560T>A	p.Met187Lys	missense	Exon 7 of 9	NP_001257889.1	Q9Y314
	NOSIP	NM_001363649.3		c.569T>A	p.Met190Lys	missense	Exon 8 of 10	NP_001350578.1	A0A075B6F9
	NOSIP	NM_001439222.1		c.569T>A	p.Met190Lys	missense	Exon 7 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.560T>A	p.Met187Lys	missense	Exon 7 of 9	ENSP00000470034.1	Q9Y314
	NOSIP	ENST00000874168.1		c.560T>A	p.Met187Lys	missense	Exon 7 of 9	ENSP00000544227.1
	NOSIP	ENST00000339093.7	TSL:5	c.569T>A	p.Met190Lys	missense	Exon 7 of 9	ENSP00000343497.3	A0A075B6F9

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1456260 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 723684

African (AFR) AF: 0.00 AC: 0 AN: 33358

American (AMR) AF: 0.00 AC: 0 AN: 44222

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26006

East Asian (EAS) AF: 0.00 AC: 0 AN: 39506

South Asian (SAS) AF: 0.0000233 AC: 2 AN: 85862

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52708

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1108788

Other (OTH) AF: 0.00 AC: 0 AN: 60052

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.36	T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.76	D
MetaRNN	Uncertain	0.73	D
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		6.7
PrimateAI	Uncertain	0.64	T
REVEL	Uncertain	0.60
Sift4G	Uncertain	0.019	D
Polyphen		1.0	D
Vest4		0.88
MutPred		0.35		Loss of ubiquitination at K190 (P = 0.0246)
MVP		0.89
ClinPred		0.97	D
GERP RS		3.6
Varity_R		0.87
gMVP		0.92
Mutation Taster		=55/45	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: rs141077974; hg19: chr19-50059971;