16-29664403-C-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6_Moderate

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 (★). 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
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.12

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]

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]

ACMG classification

Verdict is Likely_benign. Variant got -6 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 criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00281 AC: 428 AN: 152200 Hom.: 0 Cov.: 31

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.: 0 AF XY: 0.00233 AC XY: 316 AN XY: 135900

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.: 8 Cov.: 31 AF XY: 0.00368 AC XY: 2675 AN XY: 727232

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.: 0 Cov.: 31 AF XY: 0.00271 AC XY: 202 AN XY: 74482

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.: 1

Bravo AF: 0.00303

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00285 AC: 11

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

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	T
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	N
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.0048	T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.5	L;.;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.22	T
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	T
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

Other links and lift over

dbSNP: rs11574556; hg19: chr16-29675724; COSMIC: COSV64070501; COSMIC: COSV64070501;