22-32832736-T-C

Variant names:

• chr22-32832736-T-C
• rs8140818
• NM_003490.4:c.711+32179A>G

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+32179A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.103 in 151,814 control chromosomes in the GnomAD database, including 927 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 0.10 (927 hom., cov: 31)
• Consequence: SYN3 NM_003490.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.10
• Publications: 4 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=-0.94).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.165 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYN3	NM_003490.4	MANE Select	c.711+32179A>G		intron	N/A	NP_003481.3
	TIMP3	NM_000362.5	MANE Select	c.122-16716T>C		intron	N/A	NP_000353.1
	SYN3	NM_001369907.1		c.711+32179A>G		intron	N/A	NP_001356836.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYN3	ENST00000358763.7	TSL:5 MANE Select	c.711+32179A>G		intron	N/A	ENSP00000351614.2
	TIMP3	ENST00000266085.7	TSL:1 MANE Select	c.122-16716T>C		intron	N/A	ENSP00000266085.5
	SYN3	ENST00000462268.1	TSL:3	n.225+32179A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.102 AC: 15543 AN: 151696 Hom.: 924 Cov.: 31

Gnomad AFR AF: 0.168

Gnomad AMI AF: 0.0681

Gnomad AMR AF: 0.0746

Gnomad ASJ AF: 0.111

Gnomad EAS AF: 0.0526

Gnomad SAS AF: 0.0716

Gnomad FIN AF: 0.0832

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.0781

Gnomad OTH AF: 0.0983

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

GnomAD4 genome AF: 0.103 AC: 15564 AN: 151814 Hom.: 927 Cov.: 31 AF XY: 0.102 AC XY: 7563 AN XY: 74170

African (AFR) AF: 0.168 AC: 6937 AN: 41278

American (AMR) AF: 0.0743 AC: 1133 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.111 AC: 383 AN: 3466

East Asian (EAS) AF: 0.0528 AC: 272 AN: 5156

South Asian (SAS) AF: 0.0713 AC: 343 AN: 4814

European-Finnish (FIN) AF: 0.0832 AC: 878 AN: 10554

Middle Eastern (MID) AF: 0.139 AC: 41 AN: 294

European-Non Finnish (NFE) AF: 0.0781 AC: 5307 AN: 67978

Other (OTH) AF: 0.0987 AC: 208 AN: 2108

Alfa AF: 0.0944 Hom.: 109

Bravo AF: 0.107

Asia WGS AF: 0.0610 AC: 212 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.51
DANN	Benign	0.24
PhyloP100		-1.1
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: rs8140818; hg19: chr22-33228722;