2-168851367-C-T

Variant names:

• chr2-168851367-C-T
• rs200698517
• NM_001039724.4:c.818C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001039724.4(NOSTRIN):​c.818C>T​(p.Thr273Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000924 in 1,612,726 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00042 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000058 (2 hom.)
• Consequence: NOSTRIN NM_001039724.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.23
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.028291821).
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOSTRIN	NM_001039724.4	c.818C>T	p.Thr273Ile	missense_variant	Exon 10 of 16	ENST00000317647.12	NP_001034813.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOSTRIN	ENST00000317647.12	c.818C>T	p.Thr273Ile	missense_variant	Exon 10 of 16	1	NM_001039724.4	ENSP00000318921.7

Frequencies

GnomAD3 genomes AF: 0.000421 AC: 64 AN: 151956 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00138

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000973 AC: 24 AN: 246652 AF XY: 0.0000673

Gnomad AFR exome AF: 0.00130

Gnomad AMR exome AF: 0.000117

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000582 AC: 85 AN: 1460652 Hom.: 2 Cov.: 31 AF XY: 0.0000427 AC XY: 31 AN XY: 726458

African (AFR) AF: 0.00176 AC: 59 AN: 33440

American (AMR) AF: 0.000203 AC: 9 AN: 44438

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 85696

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53362

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111798

Other (OTH) AF: 0.000249 AC: 15 AN: 60348

GnomAD4 genome AF: 0.000421 AC: 64 AN: 152074 Hom.: 0 Cov.: 32 AF XY: 0.000390 AC XY: 29 AN XY: 74330

African (AFR) AF: 0.00137 AC: 57 AN: 41470

American (AMR) AF: 0.000392 AC: 6 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10554

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67990

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000157 Hom.: 0

Bravo AF: 0.000457

ESP6500AA AF: 0.00136 AC: 5

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000994 AC: 12

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 19, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.989C>T (p.T330I) alteration is located in exon 15 (coding exon 11) of the NOSTRIN gene. This alteration results from a C to T substitution at nucleotide position 989, causing the threonine (T) at amino acid position 330 to be replaced by an isoleucine (I). 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	Benign	0.13
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0043	.;.;T;.;.;.
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.10
FATHMM_MKL	Benign	0.76	D
LIST_S2	Benign	0.68	.;T;T;.;T;T
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.028	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.92	.;.;L;.;.;.
PhyloP100		1.2
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.9	N;N;N;N;N;N
REVEL	Benign	0.029
Sift	Benign	0.17	T;T;T;T;T;T
Sift4G	Benign	0.20	T;T;T;T;T;T
Polyphen		0.0040, 0.0020	.;.;B;.;.;B
Vest4		0.24
MVP		0.54
MPC		0.089
ClinPred		0.015	T
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.056
gMVP		0.20
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs200698517; hg19: chr2-169707877; COSMIC: COSV106097308; COSMIC: COSV106097308;