16-29664005-A-G

Position:

chr16-29664005-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_003123.6(SPN):c.277A>G(p.Thr93Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00344 in 1,614,010 control chromosomes in the GnomAD database, including 242 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.0049 ( 32 hom., cov: 31)

Exomes 𝑓: 0.0033 ( 210 hom. )

Consequence

SPN
NM_003123.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.204

Variant links:

Genes affected

SPN (HGNC:11249): (sialophorin) This gene encodes a highly sialylated glycoprotein that functions in antigen-specific activation of T cells, and is found on the surface of thymocytes, T lymphocytes, monocytes, granulocytes, and some B lymphocytes. It contains a mucin-like extracellular domain, a transmembrane region and a carboxy-terminal intracellular region. The extracellular domain has a high proportion of serine and threonine residues, allowing extensive O-glycosylation, and has one potential N-glycosylation site, while the carboxy-terminal region has potential phosphorylation sites that may mediate transduction of activation signals. Different glycoforms of this protein have been described. In stimulated immune cells, proteolytic cleavage of the extracellular domain occurs in some cell types, releasing a soluble extracellular fragment. Defects in expression of this gene are associated with Wiskott-Aldrich syndrome. [provided by RefSeq, Sep 2017]

SPN links:

QPRT (HGNC:9755): (quinolinate phosphoribosyltransferase) This gene encodes a key enzyme in catabolism of quinolinate, an intermediate in the tryptophan-nicotinamide adenine dinucleotide pathway. Quinolinate acts as a most potent endogenous exitotoxin to neurons. Elevation of quinolinate levels in the brain has been linked to the pathogenesis of neurodegenerative disorders such as epilepsy, Alzheimer's disease, and Huntington's disease. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Dec 2015]

QPRT 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=0.0016968548).

BP6

Variant 16-29664005-A-G is Benign according to our data. Variant chr16-29664005-A-G is described in ClinVar as [Benign]. Clinvar id is 790877.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.102 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPN	NM_003123.6 linkuse as main transcript	c.277A>G	p.Thr93Ala	missense_variant	2/2	ENST00000652691.1
SPN	NM_001030288.4 linkuse as main transcript	c.277A>G	p.Thr93Ala	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPN	ENST00000652691.1 linkuse as main transcript	c.277A>G	p.Thr93Ala	missense_variant	2/2		NM_003123.6	P1

Frequencies

GnomAD3 genomes

AF:

0.00487

AC:

741

AN:

152004

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000483

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000786

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.110

Gnomad SAS

AF:

0.00520

Gnomad FIN

AF:

0.00746

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000382

Gnomad OTH

AF:

0.00431

GnomAD3 exomes

AF:

0.00970

AC:

2440

AN:

251492

Hom.:

133

AF XY:

0.00901

AC XY:

1224

AN XY:

135920

show subpopulations

Gnomad AFR exome

AF:

0.000923

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.000595

Gnomad EAS exome

AF:

0.112

Gnomad SAS exome

AF:

0.00447

Gnomad FIN exome

AF:

0.00744

Gnomad NFE exome

AF:

0.000264

Gnomad OTH exome

AF:

0.00456

GnomAD4 exome

AF:

0.00329

AC:

4810

AN:

1461888

Hom.:

210

Cov.:

AF XY:

0.00322

AC XY:

2344

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.000358

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.000344

Gnomad4 EAS exome

AF:

0.0868

Gnomad4 SAS exome

AF:

0.00399

Gnomad4 FIN exome

AF:

0.00642

Gnomad4 NFE exome

AF:

0.000192

Gnomad4 OTH exome

AF:

0.00715

GnomAD4 genome

AF:

0.00486

AC:

739

AN:

152122

Hom.:

Cov.:

AF XY:

0.00554

AC XY:

412

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.000482

Gnomad4 AMR

AF:

0.000785

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.110

Gnomad4 SAS

AF:

0.00520

Gnomad4 FIN

AF:

0.00746

Gnomad4 NFE

AF:

0.000382

Gnomad4 OTH

AF:

0.00427

Alfa

AF:

0.00391

Hom.:

Bravo

AF:

0.00489

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00137

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.00889

AC:

1079

Asia WGS

AF:

0.0340

AC:

117

AN:

3478

EpiCase

AF:

0.000218

EpiControl

AF:

0.000296

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

SPN-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 23, 2019

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). -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jul 04, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.76

BayesDel_noAF

Benign

-0.77

CADD

Benign

0.29

DANN

Benign

0.72

DEOGEN2

Benign

0.37

T;.;T

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.043

LIST_S2

Benign

0.27

.;T;T

MetaRNN

Benign

0.0017

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.3

L;.;L

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.19

PROVEAN

Benign

-1.9

N;N;N

REVEL

Benign

0.0090

Sift

Benign

0.21

T;T;T

Sift4G

Benign

0.17

T;T;T

Polyphen

0.0010

B;.;B

Vest4

0.030

MVP

0.20

MPC

0.17

ClinPred

0.0069

GERP RS

2.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.047

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

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