Genetic Variant NOSTRIN:p.Ala316Gly (chr2-168855443-C-G) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001039724.4(NOSTRIN):c.947C>G(p.Ala316Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000152 in 1,451,562 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A316D) has been classified as Uncertain significance.

Frequency

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

Exomes 𝑓: 0.000015 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

NOSTRIN
NM_001039724.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.600

Publications

0 publications found

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 was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.06314632).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOSTRIN	NM_001039724.4 link	c.947C>G	p.Ala316Gly	missense_variant	Exon 11 of 16	ENST00000317647.12	NP_001034813.2	Q8IVI9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOSTRIN	ENST00000317647.12 link	c.947C>G	p.Ala316Gly	missense_variant	Exon 11 of 16	1	NM_001039724.4	ENSP00000318921.7		Q8IVI9-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

151928

Hom.:

Cov.:

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:

0.000623

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000324

AC:

AN:

246772

AF XY:

0.0000373

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000893

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000152

AC:

AN:

1451562

Hom.:

Cov.:

AF XY:

0.0000207

AC XY:

AN XY:

722906

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33150

American (AMR)

AF:

0.00

AC:

AN:

44342

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26002

East Asian (EAS)

AF:

0.00

AC:

AN:

39454

South Asian (SAS)

AF:

0.000245

AC:

AN:

85768

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53322

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

9.06e-7

AC:

AN:

1103772

Other (OTH)

AF:

0.00

AC:

AN:

60006

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.439

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000197

AC:

AN:

152042

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74328

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41488

American (AMR)

AF:

0.00

AC:

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.000623

AC:

AN:

4812

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10548

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67964

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.542

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000497

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.0061

.;.;T;.;.;.

Eigen

Benign

-0.031

Eigen_PC

Benign

0.028

FATHMM_MKL

Benign

0.54

LIST_S2

Uncertain

0.87

.;D;D;.;D;D

M_CAP

Benign

0.0083

MetaRNN

Benign

0.063

T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.6

.;.;M;.;.;.

PhyloP100

0.60

PrimateAI

Benign

0.32

PROVEAN

Benign

-1.5

N;N;N;N;N;N

REVEL

Benign

0.089

Sift

Benign

0.23

T;T;T;T;T;T

Sift4G

Uncertain

0.023

D;D;D;D;D;D

Polyphen

0.94, 0.95

.;.;P;.;.;P

Vest4

0.31

MutPred

0.14

.;.;Gain of ubiquitination at K318 (P = 0.0872);.;.;.;

MVP

0.46

MPC

0.097

ClinPred

0.18

GERP RS

4.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.092

gMVP

0.13

Mutation Taster

=65/35

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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2-168855443-C-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over