16-29664005-A-G

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.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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.204

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=0.0016968548).
• 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	c.277A>G	p.Thr93Ala	missense_variant	2/2	ENST00000652691.1
SPN	NM_001030288.4	c.277A>G	p.Thr93Ala	missense_variant	2/2

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00487 AC: 741 AN: 152004 Hom.: 32 Cov.: 31

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

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.: 31 AF XY: 0.00322 AC XY: 2344 AN XY: 727248

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.: 32 Cov.: 31 AF XY: 0.00554 AC XY: 412 AN XY: 74352

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.: 35

Bravo AF: 0.00489

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00137 AC: 6

ESP6500EA AF: 0.000233 AC: 2

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

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	T
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	N
MetaRNN	Benign	0.0017	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	L;.;L
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.19	T
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	T
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

Other links and lift over

dbSNP: rs2229654; hg19: chr16-29675326;