chr22-32833699-T-C

Variant names:

• chr22-32833699-T-C
• rs242077
• NM_003490.4:c.711+31216A>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+31216A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.577 in 449,510 control chromosomes in the GnomAD database, including 75,828 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 0.59 (26180 hom., cov: 32)
  • Exomes 𝑓: 0.57 (49648 hom.)
• Consequence: SYN3 NM_003490.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.508
• Publications: 7 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=-0.89).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.657 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+31216A>G		intron	N/A	NP_003481.3
	TIMP3	NM_000362.5	MANE Select	c.122-15753T>C		intron	N/A	NP_000353.1
	SYN3	NM_001369907.1		c.711+31216A>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+31216A>G		intron	N/A	ENSP00000351614.2
	TIMP3	ENST00000266085.7	TSL:1 MANE Select	c.122-15753T>C		intron	N/A	ENSP00000266085.5
	SYN3	ENST00000462268.1	TSL:3	n.225+31216A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.585 AC: 88948 AN: 151922 Hom.: 26175 Cov.: 32

Gnomad AFR AF: 0.543

Gnomad AMI AF: 0.776

Gnomad AMR AF: 0.668

Gnomad ASJ AF: 0.626

Gnomad EAS AF: 0.589

Gnomad SAS AF: 0.496

Gnomad FIN AF: 0.588

Gnomad MID AF: 0.627

Gnomad NFE AF: 0.593

Gnomad OTH AF: 0.604

GnomAD4 exome AF: 0.573 AC: 170483 AN: 297470 Hom.: 49648 AF XY: 0.562 AC XY: 95360 AN XY: 169626

African (AFR) AF: 0.529 AC: 3887 AN: 7350

American (AMR) AF: 0.700 AC: 21207 AN: 30312

Ashkenazi Jewish (ASJ) AF: 0.609 AC: 5466 AN: 8980

East Asian (EAS) AF: 0.575 AC: 4928 AN: 8570

South Asian (SAS) AF: 0.475 AC: 26922 AN: 56684

European-Finnish (FIN) AF: 0.567 AC: 7678 AN: 13538

Middle Eastern (MID) AF: 0.562 AC: 1442 AN: 2566

European-Non Finnish (NFE) AF: 0.584 AC: 91063 AN: 155874

Other (OTH) AF: 0.580 AC: 7890 AN: 13596

GnomAD4 genome AF: 0.585 AC: 88986 AN: 152040 Hom.: 26180 Cov.: 32 AF XY: 0.586 AC XY: 43549 AN XY: 74298

African (AFR) AF: 0.543 AC: 22494 AN: 41462

American (AMR) AF: 0.668 AC: 10217 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.626 AC: 2172 AN: 3472

East Asian (EAS) AF: 0.588 AC: 3034 AN: 5156

South Asian (SAS) AF: 0.495 AC: 2380 AN: 4806

European-Finnish (FIN) AF: 0.588 AC: 6204 AN: 10560

Middle Eastern (MID) AF: 0.619 AC: 182 AN: 294

European-Non Finnish (NFE) AF: 0.593 AC: 40330 AN: 67980

Other (OTH) AF: 0.602 AC: 1267 AN: 2106

Alfa AF: 0.598 Hom.: 17368

Bravo AF: 0.592

Asia WGS AF: 0.560 AC: 1944 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.55
DANN	Benign	0.41
PhyloP100		-0.51
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: rs242077; hg19: chr22-33229685;