rs2283884

Variant names:

• chr22-32852068-A-T
• rs2283884
• NM_003490.4:c.711+12847T>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003490.4(SYN3):​c.711+12847T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.262 in 152,138 control chromosomes in the GnomAD database, including 5,763 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.26 (5763 hom., cov: 33)
• Consequence: SYN3 NM_003490.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.550
• Publications: 5 publications found

Genes affected

SYN3 (HGNC:11496): (synapsin III) This gene is a member of the synapsin gene family. Synapsins encode neuronal phosphoproteins which associate with the cytoplasmic surface of synaptic vesicles. Family members are characterized by common protein domains, and they are implicated in synaptogenesis and the modulation of neurotransmitter release, suggesting a potential role in several neuropsychiatric diseases. The protein encoded by this gene shares the synapsin family domain model, with domains A, C, and E exhibiting the highest degree of conservation. The protein contains a unique domain J, located between domains C and E. Based on this gene's localization to 22q12.3, a possible schizophrenia susceptibility locus, and the established neurobiological roles of the synapsins, this family member may represent a candidate gene for schizophrenia. The TIMP3 gene is located within an intron of this gene and is transcribed in the opposite direction. Alternative splicing of this gene results in multiple splice variants that encode different isoforms. [provided by RefSeq, Oct 2008]

TIMP3 (HGNC:11822): (TIMP metallopeptidase inhibitor 3) This gene belongs to the TIMP gene family. The proteins encoded by this gene family are inhibitors of the matrix metalloproteinases, a group of peptidases involved in degradation of the extracellular matrix (ECM). Expression of this gene is induced in response to mitogenic stimulation and this netrin domain-containing protein is localized to the ECM. Mutations in this gene have been associated with the autosomal dominant disorder Sorsby's fundus dystrophy. [provided by RefSeq, Jul 2008]

TIMP3 Gene-Disease associations (from GenCC):

• Sorsby fundus dystrophy

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, ClinGen, G2P

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.388 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYN3	NM_003490.4	c.711+12847T>A		intron_variant	Intron 6 of 13	ENST00000358763.7	NP_003481.3
TIMP3	NM_000362.5	c.204+2534A>T		intron_variant	Intron 2 of 4	ENST00000266085.7	NP_000353.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYN3	ENST00000358763.7	c.711+12847T>A		intron_variant	Intron 6 of 13	5	NM_003490.4	ENSP00000351614.2
TIMP3	ENST00000266085.7	c.204+2534A>T		intron_variant	Intron 2 of 4	1	NM_000362.5	ENSP00000266085.5
SYN3	ENST00000462268.1	n.225+12847T>A		intron_variant	Intron 2 of 2	3

Frequencies

GnomAD3 genomes AF: 0.262 AC: 39766 AN: 152020 Hom.: 5754 Cov.: 33

Gnomad AFR AF: 0.372

Gnomad AMI AF: 0.326

Gnomad AMR AF: 0.325

Gnomad ASJ AF: 0.214

Gnomad EAS AF: 0.402

Gnomad SAS AF: 0.172

Gnomad FIN AF: 0.158

Gnomad MID AF: 0.187

Gnomad NFE AF: 0.195

Gnomad OTH AF: 0.243

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.262 AC: 39802 AN: 152138 Hom.: 5763 Cov.: 33 AF XY: 0.262 AC XY: 19524 AN XY: 74380

African (AFR) AF: 0.372 AC: 15417 AN: 41490

American (AMR) AF: 0.325 AC: 4971 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.214 AC: 742 AN: 3468

East Asian (EAS) AF: 0.402 AC: 2072 AN: 5148

South Asian (SAS) AF: 0.171 AC: 824 AN: 4818

European-Finnish (FIN) AF: 0.158 AC: 1678 AN: 10598

Middle Eastern (MID) AF: 0.194 AC: 57 AN: 294

European-Non Finnish (NFE) AF: 0.195 AC: 13229 AN: 68004

Other (OTH) AF: 0.243 AC: 515 AN: 2116

Alfa AF: 0.228 Hom.: 554

Bravo AF: 0.281

Asia WGS AF: 0.319 AC: 1106 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	3.7
DANN	Benign	0.27
PhyloP100		0.55
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2283884; hg19: chr22-33248055;