2-168860825-C-T

Position:

chr2-168860825-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP6BS2

The NM_001039724.4(NOSTRIN):c.1210C>T(p.Arg404Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00104 in 1,613,060 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00097 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0010 ( 2 hom. )

Consequence

NOSTRIN
NM_001039724.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 1.69

Variant links:

Genes affected

NOSTRIN (HGNC:20203): (nitric oxide synthase trafficking) Nitric oxide (NO) is a potent mediator in biologic processes such as neurotransmission, inflammatory response, and vascular homeostasis. NOSTRIN binds the enzyme responsible for NO production, endothelial NO synthase (ENOS; MIM 163729), and triggers the translocation of ENOS from the plasma membrane to vesicle-like subcellular structures, thereby attenuating ENOS-dependent NO production.[supplied by OMIM, Apr 2004]

NOSTRIN links:

SPC25 (HGNC:24031): (SPC25 component of NDC80 kinetochore complex) This gene encodes a protein that may be involved in kinetochore-microtubule interaction and spindle checkpoint activity. [provided by RefSeq, Jul 2008]

SPC25 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

BP6

Variant 2-168860825-C-T is Benign according to our data. Variant chr2-168860825-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 790256.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOSTRIN	NM_001039724.4 linkuse as main transcript	c.1210C>T	p.Arg404Trp	missense_variant	14/16	ENST00000317647.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NOSTRIN	ENST00000317647.12 linkuse as main transcript	c.1210C>T	p.Arg404Trp	missense_variant	14/16	1	NM_001039724.4	P1	Q8IVI9-1

Frequencies

GnomAD3 genomes

AF:

0.000967

AC:

147

AN:

152062

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.00548

Gnomad AMR

AF:

0.000458

Gnomad ASJ

AF:

0.00432

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00147

Gnomad OTH

AF:

0.00191

GnomAD3 exomes

AF:

0.000846

AC:

211

AN:

249446

Hom.:

AF XY:

0.000865

AC XY:

117

AN XY:

135332

show subpopulations

Gnomad AFR exome

AF:

0.000323

Gnomad AMR exome

AF:

0.000348

Gnomad ASJ exome

AF:

0.00606

Gnomad EAS exome

AF:

0.0000557

Gnomad SAS exome

AF:

0.000621

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000954

Gnomad OTH exome

AF:

0.000826

GnomAD4 exome

AF:

0.00105

AC:

1533

AN:

1460880

Hom.:

Cov.:

AF XY:

0.00110

AC XY:

800

AN XY:

726830

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

Gnomad4 AMR exome

AF:

0.000380

Gnomad4 ASJ exome

AF:

0.00578

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000522

Gnomad4 FIN exome

AF:

0.0000936

Gnomad4 NFE exome

AF:

0.00112

Gnomad4 OTH exome

AF:

0.000977

GnomAD4 genome

AF:

0.000966

AC:

147

AN:

152180

Hom.:

Cov.:

AF XY:

0.000874

AC XY:

AN XY:

74398

show subpopulations

Gnomad4 AFR

AF:

0.000337

Gnomad4 AMR

AF:

0.000458

Gnomad4 ASJ

AF:

0.00432

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00147

Gnomad4 OTH

AF:

0.00189

Alfa

AF:

0.00140

Hom.:

Bravo

AF:

0.000801

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.000816

AC:

ESP6500EA

AF:

0.00122

AC:

ExAC

AF:

0.000861

AC:

104

EpiCase

AF:

0.00125

EpiControl

AF:

0.00130

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 16, 2021

The c.1381C>T (p.R461W) alteration is located in exon 19 (coding exon 15) of the NOSTRIN gene. This alteration results from a C to T substitution at nucleotide position 1381, causing the arginine (R) at amino acid position 461 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 20, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.11

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.081

.;.;T;.;.;.

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.61

FATHMM_MKL

Uncertain

0.85

LIST_S2

Uncertain

0.95

.;D;D;.;D;D

M_CAP

Benign

0.028

MetaRNN

Benign

0.013

T;T;T;T;T;T

MetaSVM

Benign

-0.62

MutationAssessor

Uncertain

2.5

.;.;M;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D;D

PrimateAI

Benign

0.47

PROVEAN

Benign

-1.9

N;N;N;N;N;N

REVEL

Benign

0.23

Sift

Uncertain

0.0040

D;D;D;D;D;D

Sift4G

Uncertain

0.0080

D;D;D;D;D;D

Polyphen

1.0, 1.0, 0.99

.;.;D;D;D;D

Vest4

0.47

MVP

0.80

MPC

0.37

ClinPred

0.049

GERP RS

5.8

Varity_R

0.22

gMVP

0.54

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.29

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.29

Position offset: -30

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over