chr2-168860907-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001039724.4(NOSTRIN):​c.1292C>T​(p.Pro431Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00173 in 1,600,312 control chromosomes in the GnomAD database, including 57 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/24 in silico tools predict a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0095 ( 29 hom., cov: 32)
Exomes 𝑓: 0.00091 ( 28 hom. )

Consequence

NOSTRIN
NM_001039724.4 missense, splice_region

Scores

18
Splicing: ADA: 0.01083
2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.862
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 -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0035933852).
BP6
Variant 2-168860907-C-T is Benign according to our data. Variant chr2-168860907-C-T is described in ClinVar as [Benign]. Clinvar id is 783990.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00953 (1450/152218) while in subpopulation AFR AF= 0.0329 (1364/41522). AF 95% confidence interval is 0.0314. There are 29 homozygotes in gnomad4. There are 695 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 29 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
NOSTRINNM_001039724.4 linkuse as main transcriptc.1292C>T p.Pro431Leu missense_variant, splice_region_variant 14/16 ENST00000317647.12

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
NOSTRINENST00000317647.12 linkuse as main transcriptc.1292C>T p.Pro431Leu missense_variant, splice_region_variant 14/161 NM_001039724.4 P1Q8IVI9-1

Frequencies

GnomAD3 genomes
AF:
0.00949
AC:
1444
AN:
152100
Hom.:
28
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0328
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00412
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000414
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000882
Gnomad OTH
AF:
0.00718
GnomAD3 exomes
AF:
0.00239
AC:
596
AN:
249262
Hom.:
13
AF XY:
0.00184
AC XY:
249
AN XY:
135252
show subpopulations
Gnomad AFR exome
AF:
0.0351
Gnomad AMR exome
AF:
0.00131
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:
0.00000884
Gnomad OTH exome
AF:
0.000992
GnomAD4 exome
AF:
0.000907
AC:
1314
AN:
1448094
Hom.:
28
Cov.:
27
AF XY:
0.000732
AC XY:
528
AN XY:
721426
show subpopulations
Gnomad4 AFR exome
AF:
0.0339
Gnomad4 AMR exome
AF:
0.00141
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000349
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000118
Gnomad4 OTH exome
AF:
0.00182
GnomAD4 genome
AF:
0.00953
AC:
1450
AN:
152218
Hom.:
29
Cov.:
32
AF XY:
0.00934
AC XY:
695
AN XY:
74430
show subpopulations
Gnomad4 AFR
AF:
0.0329
Gnomad4 AMR
AF:
0.00412
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000414
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000882
Gnomad4 OTH
AF:
0.00710
Alfa
AF:
0.00165
Hom.:
4
Bravo
AF:
0.0109
TwinsUK
AF:
0.00
AC:
0
ALSPAC
AF:
0.000259
AC:
1
ESP6500AA
AF:
0.0350
AC:
132
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.00290
AC:
350
Asia WGS
AF:
0.00231
AC:
8
AN:
3478
EpiCase
AF:
0.0000546
EpiControl
AF:
0.00

ClinVar

Significance: Benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:2
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpMar 29, 2018- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.067
BayesDel_addAF
Benign
-0.64
T
BayesDel_noAF
Benign
-0.67
CADD
Benign
21
DANN
Benign
0.62
DEOGEN2
Benign
0.014
.;.;T;.;.;.
Eigen
Benign
-0.62
Eigen_PC
Benign
-0.49
FATHMM_MKL
Benign
0.25
N
LIST_S2
Benign
0.69
.;T;T;.;T;T
MetaRNN
Benign
0.0036
T;T;T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
-0.60
.;.;N;.;.;.
MutationTaster
Benign
0.59
N;N;N;N;N;N;N
PrimateAI
Benign
0.23
T
PROVEAN
Benign
-2.1
N;N;N;N;N;N
REVEL
Benign
0.092
Sift
Benign
0.31
T;T;T;T;T;T
Sift4G
Benign
0.36
T;T;T;T;T;T
Polyphen
0.0
.;.;B;B;B;B
Vest4
0.059
MVP
0.59
MPC
0.082
ClinPred
0.0079
T
GERP RS
3.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.041
gMVP
0.32

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.011
dbscSNV1_RF
Benign
0.39
SpliceAI score (max)
0.40
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.40
Position offset: 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: rs61730433; hg19: chr2-169717417; COSMIC: COSV99048184; COSMIC: COSV99048184; API