chr22-32805668-C-T

Variant names:

• chr22-32805668-C-T
• rs130269
• NM_003490.4:c.711+59247G>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+59247G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.157 in 149,562 control chromosomes in the GnomAD database, including 2,353 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 0.16 (2353 hom., cov: 27)
• Consequence: SYN3 NM_003490.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.157
• Publications: 2 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), Ambry Genetics, Orphanet, PanelApp Australia, G2P, ClinGen

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.339 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003490.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYN3	NM_003490.4	MANE Select	c.711+59247G>A		intron	N/A	NP_003481.3
	TIMP3	NM_000362.5	MANE Select	c.121+3546C>T		intron	N/A	NP_000353.1	P35625
	SYN3	NM_001369907.1		c.711+59247G>A		intron	N/A	NP_001356836.1	O14994

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYN3	ENST00000358763.7	TSL:5 MANE Select	c.711+59247G>A		intron	N/A	ENSP00000351614.2	O14994
	TIMP3	ENST00000266085.7	TSL:1 MANE Select	c.121+3546C>T		intron	N/A	ENSP00000266085.5	P35625
	TIMP3	ENST00000908983.1		c.121+3546C>T		intron	N/A	ENSP00000579042.1

Frequencies

GnomAD3 genomes AF: 0.157 AC: 23423 AN: 149446 Hom.: 2348 Cov.: 27

Gnomad AFR AF: 0.0351

Gnomad AMI AF: 0.102

Gnomad AMR AF: 0.165

Gnomad ASJ AF: 0.149

Gnomad EAS AF: 0.353

Gnomad SAS AF: 0.295

Gnomad FIN AF: 0.235

Gnomad MID AF: 0.145

Gnomad NFE AF: 0.193

Gnomad OTH AF: 0.165

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

GnomAD4 genome AF: 0.157 AC: 23423 AN: 149562 Hom.: 2353 Cov.: 27 AF XY: 0.162 AC XY: 11790 AN XY: 72854

African (AFR) AF: 0.0350 AC: 1424 AN: 40708

American (AMR) AF: 0.165 AC: 2461 AN: 14954

Ashkenazi Jewish (ASJ) AF: 0.149 AC: 513 AN: 3448

East Asian (EAS) AF: 0.352 AC: 1746 AN: 4954

South Asian (SAS) AF: 0.295 AC: 1354 AN: 4590

European-Finnish (FIN) AF: 0.235 AC: 2399 AN: 10224

Middle Eastern (MID) AF: 0.149 AC: 43 AN: 288

European-Non Finnish (NFE) AF: 0.193 AC: 13043 AN: 67436

Other (OTH) AF: 0.169 AC: 348 AN: 2058

Alfa AF: 0.0888 Hom.: 147

Bravo AF: 0.147

Asia WGS AF: 0.293 AC: 1023 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	12
DANN	Benign	0.79
PhyloP100		0.16
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: rs130269; hg19: chr22-33201654;