16-29663793-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003123.6(SPN):c.65C>T(p.Thr22Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00425 in 1,613,408 control chromosomes in the GnomAD database, including 211 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 0.021 (106 hom., cov: 31)
  • Exomes 𝑓: 0.0025 (105 hom.)
• Consequence: SPN NM_003123.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.721

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0021079779).
• BP6: Variant 16-29663793-C-T is Benign according to our data. Variant chr16-29663793-C-T is described in ClinVar as [Benign]. Clinvar id is 717407.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0716 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SPN	NM_003123.6	c.65C>T	p.Thr22Ile	missense_variant	2/2	ENST00000652691.1
SPN	NM_001030288.4	c.65C>T	p.Thr22Ile	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SPN	ENST00000652691.1	c.65C>T	p.Thr22Ile	missense_variant	2/2		NM_003123.6	P1

Frequencies

GnomAD3 genomes AF: 0.0214 AC: 3255 AN: 152088 Hom.: 106 Cov.: 31

Gnomad AFR AF: 0.0739

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.00747

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000412

Gnomad OTH AF: 0.0153

GnomAD3 exomes AF: 0.00561 AC: 1406 AN: 250608 Hom.: 51 AF XY: 0.00431 AC XY: 584 AN XY: 135428

Gnomad AFR exome AF: 0.0738

Gnomad AMR exome AF: 0.00395

Gnomad ASJ exome AF: 0.00120

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000265

Gnomad OTH exome AF: 0.00360

GnomAD4 exome AF: 0.00247 AC: 3605 AN: 1461202 Hom.: 105 Cov.: 31 AF XY: 0.00216 AC XY: 1572 AN XY: 726904

Gnomad4 AFR exome AF: 0.0791

Gnomad4 AMR exome AF: 0.00442

Gnomad4 ASJ exome AF: 0.00173

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000244

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000272

Gnomad4 OTH exome AF: 0.00615

GnomAD4 genome AF: 0.0214 AC: 3260 AN: 152206 Hom.: 106 Cov.: 31 AF XY: 0.0206 AC XY: 1532 AN XY: 74422

Gnomad4 AFR AF: 0.0738

Gnomad4 AMR AF: 0.00746

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000412

Gnomad4 OTH AF: 0.0152

Alfa AF: 0.00408 Hom.: 29

Bravo AF: 0.0249

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0737 AC: 324

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.00679 AC: 824

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000296

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

SPN-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 03, 2020

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 13, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.77
Cadd	Benign	0.92
Dann	Benign	0.60
DEOGEN2	Benign	0.29	T;.;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.037	N
MetaRNN	Benign	0.0021	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.63	N;.;N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-1.8	N;N;N
REVEL	Benign	0.0040
Sift	Benign	0.25	T;T;T
Sift4G	Benign	0.15	T;T;T
Polyphen		0.0040	B;.;B
Vest4		0.092
MVP		0.12
MPC		0.19
ClinPred		0.00014	T
GERP RS		-4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.035

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

Other links and lift over

dbSNP: rs2229653; hg19: chr16-29675114;