19-49556340-G-T

Variant names:

• chr19-49556340-G-T
• rs762959254
• NM_001270960.2:c.811C>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001270960.2(NOSIP):​c.811C>A​(p.Arg271Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,104 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign 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. R271C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NOSIP NM_001270960.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.07
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3309716).

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.811C>A	p.Arg271Ser	missense	Exon 8 of 9	NP_001257889.1	Q9Y314
	NOSIP	NM_001363649.3		c.820C>A	p.Arg274Ser	missense	Exon 9 of 10	NP_001350578.1	A0A075B6F9
	NOSIP	NM_001439222.1		c.820C>A	p.Arg274Ser	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.811C>A	p.Arg271Ser	missense	Exon 8 of 9	ENSP00000470034.1	Q9Y314
	NOSIP	ENST00000874168.1		c.838C>A	p.Arg280Ser	missense	Exon 8 of 9	ENSP00000544227.1
	NOSIP	ENST00000339093.7	TSL:5	c.820C>A	p.Arg274Ser	missense	Exon 8 of 9	ENSP00000343497.3	A0A075B6F9

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461104 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726878

African (AFR) AF: 0.00 AC: 0 AN: 33468

American (AMR) AF: 0.00 AC: 0 AN: 44658

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86216

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53226

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

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111614

Other (OTH) AF: 0.00 AC: 0 AN: 60358

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.029	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	21
DANN	Benign	0.94
DEOGEN2	Benign	0.039	T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.061
FATHMM_MKL	Benign	0.56	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.33	T
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	0.69	N
PhyloP100		4.1
PrimateAI	Benign	0.43	T
REVEL	Benign	0.26
Sift4G	Benign	0.50	T
Polyphen		0.022	B
Vest4		0.30
MutPred		0.42		Gain of methylation at K267 (P = 0.0604)
MVP		0.94
ClinPred		0.55	D
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.30
gMVP		0.65
Mutation Taster		=69/31	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: rs762959254; hg19: chr19-50059597;