2-168855443-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001039724.4(NOSTRIN):​c.947C>A​(p.Ala316Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000964 in 1,451,564 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

NOSTRIN
NM_001039724.4 missense

Scores

5
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.600
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 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.3812271).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
NOSTRINNM_001039724.4 linkuse as main transcriptc.947C>A p.Ala316Asp missense_variant 11/16 ENST00000317647.12

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
NOSTRINENST00000317647.12 linkuse as main transcriptc.947C>A p.Ala316Asp missense_variant 11/161 NM_001039724.4 P1Q8IVI9-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
0.00000964
AC:
14
AN:
1451564
Hom.:
0
Cov.:
27
AF XY:
0.00000553
AC XY:
4
AN XY:
722906
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000117
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000118
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
EpiCase
AF:
0.0000549
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 GeneticsMar 29, 2024The c.1118C>A (p.A373D) alteration is located in exon 16 (coding exon 12) of the NOSTRIN gene. This alteration results from a C to A substitution at nucleotide position 1118, causing the alanine (A) at amino acid position 373 to be replaced by an aspartic acid (D). 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
Uncertain
0.52
BayesDel_addAF
Benign
-0.11
T
BayesDel_noAF
Benign
-0.40
CADD
Benign
22
DANN
Uncertain
1.0
DEOGEN2
Benign
0.0026
.;.;T;.;.;.
Eigen
Benign
0.16
Eigen_PC
Benign
0.15
FATHMM_MKL
Benign
0.52
D
LIST_S2
Uncertain
0.86
.;D;D;.;D;D
M_CAP
Benign
0.012
T
MetaRNN
Benign
0.38
T;T;T;T;T;T
MetaSVM
Benign
-0.93
T
MutationAssessor
Uncertain
2.6
.;.;M;.;.;.
MutationTaster
Benign
1.0
D;D;D;D;D;D;D
PrimateAI
Benign
0.38
T
PROVEAN
Benign
0.080
N;N;N;N;N;N
REVEL
Benign
0.12
Sift
Benign
0.064
T;T;T;T;T;T
Sift4G
Uncertain
0.0040
D;D;D;D;D;D
Polyphen
0.88, 0.91
.;.;P;.;.;P
Vest4
0.54
MutPred
0.25
.;.;Gain of solvent accessibility (P = 0.0109);.;.;.;
MVP
0.56
MPC
0.43
ClinPred
0.93
D
GERP RS
4.4
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.12
gMVP
0.37

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: rs552601152; hg19: chr2-169711953; API