rs6518799

Variant names:

• chr22-32833610-G-A
• rs6518799
• NM_003490.4:c.711+31305C>T

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+31305C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.106 in 152,188 control chromosomes in the GnomAD database, including 1,024 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 0.11 (1024 hom., cov: 32)
• Consequence: SYN3 NM_003490.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.00
• 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 (AFR) allele frequency at 95% confidence interval = 0.177 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYN3	NM_003490.4	c.711+31305C>T		intron_variant	Intron 6 of 13	ENST00000358763.7	NP_003481.3
TIMP3	NM_000362.5	c.122-15842G>A		intron_variant	Intron 1 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+31305C>T		intron_variant	Intron 6 of 13	5	NM_003490.4	ENSP00000351614.2
TIMP3	ENST00000266085.7	c.122-15842G>A		intron_variant	Intron 1 of 4	1	NM_000362.5	ENSP00000266085.5
SYN3	ENST00000462268.1	n.225+31305C>T		intron_variant	Intron 2 of 2	3

Frequencies

GnomAD3 genomes AF: 0.106 AC: 16103 AN: 152070 Hom.: 1022 Cov.: 32

Gnomad AFR AF: 0.180

Gnomad AMI AF: 0.0680

Gnomad AMR AF: 0.0750

Gnomad ASJ AF: 0.111

Gnomad EAS AF: 0.0521

Gnomad SAS AF: 0.0721

Gnomad FIN AF: 0.0828

Gnomad MID AF: 0.133

Gnomad NFE AF: 0.0780

Gnomad OTH AF: 0.103

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

GnomAD4 genome AF: 0.106 AC: 16126 AN: 152188 Hom.: 1024 Cov.: 32 AF XY: 0.105 AC XY: 7829 AN XY: 74416

African (AFR) AF: 0.180 AC: 7482 AN: 41492

American (AMR) AF: 0.0747 AC: 1143 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.111 AC: 385 AN: 3472

East Asian (EAS) AF: 0.0522 AC: 270 AN: 5174

South Asian (SAS) AF: 0.0717 AC: 346 AN: 4824

European-Finnish (FIN) AF: 0.0828 AC: 877 AN: 10596

Middle Eastern (MID) AF: 0.136 AC: 40 AN: 294

European-Non Finnish (NFE) AF: 0.0780 AC: 5303 AN: 68010

Other (OTH) AF: 0.103 AC: 218 AN: 2112

Alfa AF: 0.0830 Hom.: 351

Bravo AF: 0.111

Asia WGS AF: 0.0610 AC: 214 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	0.34
DANN	Benign	0.30
PhyloP100		-1.0
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: rs6518799; hg19: chr22-33229596;