2-168851367-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001039724.4(NOSTRIN):​c.818C>T​(p.Thr273Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000924 in 1,612,726 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00042 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000058 ( 2 hom. )

Consequence

NOSTRIN
NM_001039724.4 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.23
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]
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.028291821).
BS2
High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
NOSTRINNM_001039724.4 linkuse as main transcriptc.818C>T p.Thr273Ile missense_variant 10/16 ENST00000317647.12

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
NOSTRINENST00000317647.12 linkuse as main transcriptc.818C>T p.Thr273Ile missense_variant 10/161 NM_001039724.4 P1Q8IVI9-1

Frequencies

GnomAD3 genomes
AF:
0.000421
AC:
64
AN:
151956
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00138
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000393
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.0000973
AC:
24
AN:
246652
Hom.:
0
AF XY:
0.0000673
AC XY:
9
AN XY:
133746
show subpopulations
Gnomad AFR exome
AF:
0.00130
Gnomad AMR exome
AF:
0.000117
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000582
AC:
85
AN:
1460652
Hom.:
2
Cov.:
31
AF XY:
0.0000427
AC XY:
31
AN XY:
726458
show subpopulations
Gnomad4 AFR exome
AF:
0.00176
Gnomad4 AMR exome
AF:
0.000203
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:
0.00000180
Gnomad4 OTH exome
AF:
0.000249
GnomAD4 genome
AF:
0.000421
AC:
64
AN:
152074
Hom.:
0
Cov.:
32
AF XY:
0.000390
AC XY:
29
AN XY:
74330
show subpopulations
Gnomad4 AFR
AF:
0.00137
Gnomad4 AMR
AF:
0.000392
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.0000783
Hom.:
0
Bravo
AF:
0.000457
ESP6500AA
AF:
0.00136
AC:
5
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000994
AC:
12

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsDec 19, 2023The c.989C>T (p.T330I) alteration is located in exon 15 (coding exon 11) of the NOSTRIN gene. This alteration results from a C to T substitution at nucleotide position 989, causing the threonine (T) at amino acid position 330 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
0.13
BayesDel_addAF
Benign
-0.57
T
BayesDel_noAF
Benign
-0.61
CADD
Benign
20
DANN
Uncertain
0.99
DEOGEN2
Benign
0.0043
.;.;T;.;.;.
Eigen
Benign
-0.26
Eigen_PC
Benign
-0.10
FATHMM_MKL
Benign
0.76
D
LIST_S2
Benign
0.68
.;T;T;.;T;T
M_CAP
Benign
0.0051
T
MetaRNN
Benign
0.028
T;T;T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.92
.;.;L;.;.;.
MutationTaster
Benign
0.98
N;N;N;N;N;N;N
PrimateAI
Benign
0.36
T
PROVEAN
Benign
-1.9
N;N;N;N;N;N
REVEL
Benign
0.029
Sift
Benign
0.17
T;T;T;T;T;T
Sift4G
Benign
0.20
T;T;T;T;T;T
Polyphen
0.0040, 0.0020
.;.;B;.;.;B
Vest4
0.24
MVP
0.54
MPC
0.089
ClinPred
0.015
T
GERP RS
4.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.056
gMVP
0.20

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

LitVar

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

Other links and lift over

dbSNP: rs200698517; hg19: chr2-169707877; API