NM_003490.4:c.711+58423T>C

Variant names:

• chr22-32806492-A-G
• rs135025
• NM_003490.4:c.711+58423T>C

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+58423T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.588 in 152,004 control chromosomes in the GnomAD database, including 26,633 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 (26633 hom., cov: 31)
• Consequence: SYN3 NM_003490.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.320
• 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=-0.83).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.671 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+58423T>C		intron	N/A	NP_003481.3
	TIMP3	NM_000362.5	MANE Select	c.121+4370A>G		intron	N/A	NP_000353.1
	SYN3	NM_001369907.1		c.711+58423T>C		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+58423T>C		intron	N/A	ENSP00000351614.2
	TIMP3	ENST00000266085.7	TSL:1 MANE Select	c.121+4370A>G		intron	N/A	ENSP00000266085.5
	SYN3	ENST00000462268.1	TSL:3	n.225+58423T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.588 AC: 89279 AN: 151884 Hom.: 26588 Cov.: 31

Gnomad AFR AF: 0.677

Gnomad AMI AF: 0.507

Gnomad AMR AF: 0.561

Gnomad ASJ AF: 0.589

Gnomad EAS AF: 0.462

Gnomad SAS AF: 0.544

Gnomad FIN AF: 0.549

Gnomad MID AF: 0.604

Gnomad NFE AF: 0.559

Gnomad OTH AF: 0.601

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

GnomAD4 genome AF: 0.588 AC: 89385 AN: 152004 Hom.: 26633 Cov.: 31 AF XY: 0.586 AC XY: 43516 AN XY: 74288

African (AFR) AF: 0.677 AC: 28099 AN: 41476

American (AMR) AF: 0.562 AC: 8579 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.589 AC: 2043 AN: 3468

East Asian (EAS) AF: 0.462 AC: 2384 AN: 5158

South Asian (SAS) AF: 0.544 AC: 2611 AN: 4804

European-Finnish (FIN) AF: 0.549 AC: 5803 AN: 10562

Middle Eastern (MID) AF: 0.616 AC: 181 AN: 294

European-Non Finnish (NFE) AF: 0.559 AC: 37953 AN: 67944

Other (OTH) AF: 0.602 AC: 1271 AN: 2112

Alfa AF: 0.549 Hom.: 17440

Bravo AF: 0.605

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.76
DANN	Benign	0.45
PhyloP100		-0.32
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: rs135025; hg19: chr22-33202478;