2-168864917-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001039724.4(NOSTRIN):​c.1468G>A​(p.Ala490Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000527 in 1,614,078 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000056 ( 1 hom. )

Consequence

NOSTRIN
NM_001039724.4 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.60
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 Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.12590018).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
NOSTRINNM_001039724.4 linkuse as main transcriptc.1468G>A p.Ala490Thr missense_variant 16/16 ENST00000317647.12

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
NOSTRINENST00000317647.12 linkuse as main transcriptc.1468G>A p.Ala490Thr missense_variant 16/161 NM_001039724.4 P1Q8IVI9-1

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152142
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000120
AC:
3
AN:
249480
Hom.:
0
AF XY:
0.0000148
AC XY:
2
AN XY:
135354
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000327
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000177
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000561
AC:
82
AN:
1461818
Hom.:
1
Cov.:
32
AF XY:
0.0000578
AC XY:
42
AN XY:
727222
show subpopulations
Gnomad4 AFR exome
AF:
0.000119
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000464
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000612
Gnomad4 OTH exome
AF:
0.0000994
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152260
Hom.:
0
Cov.:
32
AF XY:
0.0000269
AC XY:
2
AN XY:
74448
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000773
Hom.:
0
Bravo
AF:
0.0000189
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000121
AC:
1
ExAC
AF:
0.00000827
AC:
1
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

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 GeneticsMay 30, 2024The c.1639G>A (p.A547T) alteration is located in exon 21 (coding exon 17) of the NOSTRIN gene. This alteration results from a G to A substitution at nucleotide position 1639, causing the alanine (A) at amino acid position 547 to be replaced by a threonine (T). 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
0.14
BayesDel_addAF
Benign
-0.23
T
BayesDel_noAF
Benign
-0.47
CADD
Benign
14
DANN
Benign
0.87
DEOGEN2
Benign
0.012
.;.;T;.;.;.
Eigen
Benign
-0.25
Eigen_PC
Benign
-0.061
FATHMM_MKL
Benign
0.59
D
LIST_S2
Uncertain
0.91
.;D;D;.;D;D
M_CAP
Benign
0.0048
T
MetaRNN
Benign
0.13
T;T;T;T;T;T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
-0.085
.;.;N;.;.;.
MutationTaster
Benign
0.84
N;N;N;N;N;N;N
PrimateAI
Benign
0.42
T
PROVEAN
Benign
2.0
N;N;N;N;N;N
REVEL
Benign
0.077
Sift
Benign
1.0
T;T;T;T;T;T
Sift4G
Benign
0.64
T;T;T;T;T;T
Polyphen
0.13, 0.048, 0.28
.;.;B;B;B;B
Vest4
0.22
MVP
0.58
MPC
0.084
ClinPred
0.39
T
GERP RS
5.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.071
gMVP
0.25

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

Publications

LitVar

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

Other links and lift over

dbSNP: rs377563077; hg19: chr2-169721427; API