16-29664403-C-G

Position:

chr16-29664403-C-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_003123.6(SPN):c.675C>G(p.Ser225Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00367 in 1,614,184 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars). Synonymous variant affecting the same amino acid position (i.e. S225S) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0028 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0038 ( 8 hom. )

Consequence

SPN
NM_003123.6 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.12

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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.004766196).

BP6

Variant 16-29664403-C-G is Benign according to our data. Variant chr16-29664403-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 3037910.Status of the report is no_assertion_criteria_provided, 0 stars.

BS2

High Homozygotes in GnomAdExome4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPN	NM_003123.6 linkuse as main transcript	c.675C>G	p.Ser225Arg	missense_variant	2/2	ENST00000652691.1
SPN	NM_001030288.4 linkuse as main transcript	c.675C>G	p.Ser225Arg	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPN	ENST00000652691.1 linkuse as main transcript	c.675C>G	p.Ser225Arg	missense_variant	2/2		NM_003123.6	P1

Frequencies

GnomAD3 genomes

AF:

0.00281

AC:

428

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00111

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00694

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000282

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00378

Gnomad OTH

AF:

0.00478

GnomAD3 exomes

AF:

0.00238

AC:

598

AN:

251422

Hom.:

AF XY:

0.00233

AC XY:

316

AN XY:

135900

show subpopulations

Gnomad AFR exome

AF:

0.000984

Gnomad AMR exome

AF:

0.00387

Gnomad ASJ exome

AF:

0.000992

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.00365

Gnomad OTH exome

AF:

0.00326

GnomAD4 exome

AF:

0.00376

AC:

5492

AN:

1461866

Hom.:

Cov.:

AF XY:

0.00368

AC XY:

2675

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.000568

Gnomad4 AMR exome

AF:

0.00425

Gnomad4 ASJ exome

AF:

0.00172

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.000206

Gnomad4 NFE exome

AF:

0.00446

Gnomad4 OTH exome

AF:

0.00426

GnomAD4 genome

AF:

0.00281

AC:

428

AN:

152318

Hom.:

Cov.:

AF XY:

0.00271

AC XY:

202

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.00111

Gnomad4 AMR

AF:

0.00693

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000282

Gnomad4 NFE

AF:

0.00378

Gnomad4 OTH

AF:

0.00473

Alfa

AF:

0.000711

Hom.:

Bravo

AF:

0.00303

TwinsUK

AF:

0.00485

AC:

ALSPAC

AF:

0.00285

AC:

ExAC

AF:

0.00198

AC:

240

EpiCase

AF:

0.00311

EpiControl

AF:

0.00397

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

SPN-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 07, 2022

This variant is classified as likely 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

AlphaMissense

Uncertain

0.37

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.51

CADD

Benign

0.10

DANN

Benign

0.67

DEOGEN2

Benign

0.32

T;.;T

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.0065

LIST_S2

Benign

0.33

.;T;T

M_CAP

Benign

0.041

MetaRNN

Benign

0.0048

T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

1.5

L;.;L

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.22

PROVEAN

Benign

-1.3

N;N;N

REVEL

Benign

0.12

Sift

Benign

0.32

T;T;T

Sift4G

Benign

0.26

T;T;T

Polyphen

0.013

B;.;B

Vest4

0.11

MutPred

0.22

Gain of MoRF binding (P = 0.0148);Gain of MoRF binding (P = 0.0148);Gain of MoRF binding (P = 0.0148);

MVP

0.50

MPC

0.71

ClinPred

0.0065

GERP RS

-3.9

Varity_R

0.087

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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