2-168860907-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

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, single submitter B:1
• Conservation: PhyloP100: 0.862

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

Verdict is Benign. Variant got -14 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_single_submitter, 1 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 GnomAd at 28 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NOSTRIN	NM_001039724.4	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	c.1292C>T	p.Pro431Leu	missense_variant, splice_region_variant	14/16	1	NM_001039724.4	P1

Frequencies

GnomAD3 genomes AF: 0.00949 AC: 1444 AN: 152100 Hom.: 28 Cov.: 32

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

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

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

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:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Mar 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
Eigen	Benign	-0.62
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.25	N
MetaRNN	Benign	0.0036	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
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

Other links and lift over

dbSNP: rs61730433; hg19: chr2-169717417; COSMIC: COSV99048184; COSMIC: COSV99048184;