2-168860907-C-T

Position:

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

Splicing: ADA: 0.01083

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]

NOSTRIN links:

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]

SPC25 links:

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
NOSTRIN	NM_001039724.4 linkuse as main transcript	c.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
NOSTRIN	ENST00000317647.12 linkuse as main transcript	c.1292C>T	p.Pro431Leu	missense_variant, splice_region_variant	14/16	1	NM_001039724.4	P1	Q8IVI9-1

Frequencies

GnomAD3 genomes

AF:

0.00949

AC:

1444

AN:

152100

Hom.:

Cov.:

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.:

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.:

Cov.:

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.:

Cov.:

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.:

Bravo

AF:

0.0109

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0350

AC:

132

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00290

AC:

350

Asia WGS

AF:

0.00231

AC:

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 submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 29, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.67

CADD

Benign

DANN

Benign

0.62

DEOGEN2

Benign

0.014

.;.;T;.;.;.

Eigen

Benign

-0.62

Eigen_PC

Benign

-0.49

FATHMM_MKL

Benign

0.25

LIST_S2

Benign

0.69

.;T;T;.;T;T

MetaRNN

Benign

0.0036

T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.60

.;.;N;.;.;.

MutationTaster

Benign

0.59

N;N;N;N;N;N;N

PrimateAI

Benign

0.23

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

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over