2-168856702-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001039724.4(NOSTRIN):ā€‹c.977T>Cā€‹(p.Met326Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000752 in 1,461,838 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā˜…). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M326I) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.0000075 ( 0 hom. )

Consequence

NOSTRIN
NM_001039724.4 missense

Scores

9
10

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.79
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 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
NOSTRINNM_001039724.4 linkuse as main transcriptc.977T>C p.Met326Thr missense_variant 12/16 ENST00000317647.12

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
NOSTRINENST00000317647.12 linkuse as main transcriptc.977T>C p.Met326Thr missense_variant 12/161 NM_001039724.4 P1Q8IVI9-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.0000120
AC:
3
AN:
249512
Hom.:
0
AF XY:
0.00000739
AC XY:
1
AN XY:
135372
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:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000265
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000752
AC:
11
AN:
1461838
Hom.:
0
Cov.:
30
AF XY:
0.00000550
AC XY:
4
AN XY:
727226
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:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000989
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
ExAC
AF:
0.00000827
AC:
1

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 GeneticsAug 10, 2021The c.1148T>C (p.M383T) alteration is located in exon 17 (coding exon 13) of the NOSTRIN gene. This alteration results from a T to C substitution at nucleotide position 1148, causing the methionine (M) at amino acid position 383 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
Uncertain
0.48
BayesDel_addAF
Benign
-0.14
T
BayesDel_noAF
Benign
-0.37
CADD
Benign
21
DANN
Uncertain
0.98
DEOGEN2
Benign
0.063
.;.;T;.;.;.
Eigen
Benign
-0.040
Eigen_PC
Benign
0.012
FATHMM_MKL
Uncertain
0.81
D
LIST_S2
Benign
0.82
.;T;T;.;T;T
M_CAP
Benign
0.014
T
MetaRNN
Uncertain
0.62
D;D;D;D;D;D
MetaSVM
Benign
-1.1
T
MutationAssessor
Uncertain
2.6
.;.;M;.;.;.
MutationTaster
Benign
0.99
D;D;D;D;D;D;D
PrimateAI
Uncertain
0.56
T
PROVEAN
Uncertain
-3.4
D;D;D;D;D;D
REVEL
Benign
0.098
Sift
Uncertain
0.0050
D;D;D;D;D;D
Sift4G
Uncertain
0.010
D;D;D;D;D;D
Polyphen
0.36, 0.35, 0.43
.;.;B;B;B;B
Vest4
0.61
MutPred
0.27
.;.;Loss of stability (P = 0.0111);.;.;.;
MVP
0.68
MPC
0.26
ClinPred
0.90
D
GERP RS
3.8
Varity_R
0.37
gMVP
0.55

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: rs761717143; hg19: chr2-169713212; API