17-27758905-G-A

Variant names:

• chr17-27758905-G-A
• rs3729662
• NM_000625.4:c.3330C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000625.4(NOS2):​c.3330C>T​(p.Val1110Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00221 in 1,606,666 control chromosomes in the GnomAD database, including 59 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (30 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (29 hom.)
• Consequence: NOS2 NM_000625.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.34
• Publications: 4 publications found

Genes affected

NOS2 (HGNC:7873): (nitric oxide synthase 2) Nitric oxide is a reactive free radical which acts as a biologic mediator in several processes, including neurotransmission and antimicrobial and antitumoral activities. This gene encodes a nitric oxide synthase which is expressed in liver and is inducible by a combination of lipopolysaccharide and certain cytokines. Three related pseudogenes are located within the Smith-Magenis syndrome region on chromosome 17. [provided by RefSeq, Jul 2008]

NOS2 Gene-Disease associations (from GenCC):

• schizophrenia

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 17-27758905-G-A is Benign according to our data. Variant chr17-27758905-G-A is described in ClinVar as [Benign]. Clinvar id is 710107.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.34 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0119 (1814/152322) while in subpopulation AFR AF = 0.041 (1703/41582). AF 95% confidence interval is 0.0393. There are 30 homozygotes in GnomAd4. There are 852 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 30 Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOS2	NM_000625.4	c.3330C>T	p.Val1110Val	synonymous_variant	Exon 26 of 27	ENST00000313735.11	NP_000616.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOS2	ENST00000313735.11	c.3330C>T	p.Val1110Val	synonymous_variant	Exon 26 of 27	1	NM_000625.4	ENSP00000327251.6

Frequencies

GnomAD3 genomes AF: 0.0119 AC: 1808 AN: 152206 Hom.: 30 Cov.: 33

Gnomad AFR AF: 0.0409

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00543

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00526

GnomAD2 exomes AF: 0.00285 AC: 693 AN: 242800 AF XY: 0.00208

Gnomad AFR exome AF: 0.0383

Gnomad AMR exome AF: 0.00197

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000471

Gnomad NFE exome AF: 0.000119

Gnomad OTH exome AF: 0.00103

GnomAD4 exome AF: 0.00119 AC: 1735 AN: 1454344 Hom.: 29 Cov.: 31 AF XY: 0.00105 AC XY: 760 AN XY: 723294

African (AFR) AF: 0.0402 AC: 1336 AN: 33204

American (AMR) AF: 0.00193 AC: 85 AN: 43944

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25650

East Asian (EAS) AF: 0.00 AC: 0 AN: 39310

South Asian (SAS) AF: 0.000117 AC: 10 AN: 85182

European-Finnish (FIN) AF: 0.0000379 AC: 2 AN: 52766

Middle Eastern (MID) AF: 0.00229 AC: 13 AN: 5676

European-Non Finnish (NFE) AF: 0.000105 AC: 116 AN: 1108522

Other (OTH) AF: 0.00288 AC: 173 AN: 60090

GnomAD4 genome AF: 0.0119 AC: 1814 AN: 152322 Hom.: 30 Cov.: 33 AF XY: 0.0114 AC XY: 852 AN XY: 74478

African (AFR) AF: 0.0410 AC: 1703 AN: 41582

American (AMR) AF: 0.00542 AC: 83 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68026

Other (OTH) AF: 0.00521 AC: 11 AN: 2112

Alfa AF: 0.00600 Hom.: 8

Bravo AF: 0.0130

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Dec 31, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

NOS2-related disorder Benign:1

Sep 17, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.21
DANN	Benign	0.90
PhyloP100		-1.3
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs3729662; hg19: chr17-26085931;