NM_003490.4:c.711+1798T>C

Variant names:

• chr22-32863117-A-G
• rs137487
• NM_003490.4:c.711+1798T>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+1798T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.582 in 152,450 control chromosomes in the GnomAD database, including 26,673 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 0.58 (26638 hom., cov: 32)
  • Exomes 𝑓: 0.44 (35 hom.)
• Consequence: SYN3 NM_003490.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.696
• Publications: 13 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=-0.87).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.715 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+1798T>C		intron	N/A	NP_003481.3
	SYN3	NM_001369907.1		c.711+1798T>C		intron	N/A	NP_001356836.1	O14994
	SYN3	NM_001369908.1		c.711+1798T>C		intron	N/A	NP_001356837.1	O14994

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYN3	ENST00000358763.7	TSL:5 MANE Select	c.711+1798T>C		intron	N/A	ENSP00000351614.2	O14994
	SYN3	ENST00000462268.1	TSL:3	n.225+1798T>C		intron	N/A
	TIMP3	ENST00000266085.7	TSL:1 MANE Select	c.*3740A>G		downstream_gene	N/A	ENSP00000266085.5	P35625

Frequencies

GnomAD3 genomes AF: 0.582 AC: 88425 AN: 151900 Hom.: 26590 Cov.: 32

Gnomad AFR AF: 0.722

Gnomad AMI AF: 0.599

Gnomad AMR AF: 0.659

Gnomad ASJ AF: 0.545

Gnomad EAS AF: 0.586

Gnomad SAS AF: 0.370

Gnomad FIN AF: 0.444

Gnomad MID AF: 0.513

Gnomad NFE AF: 0.518

Gnomad OTH AF: 0.569

GnomAD4 exome AF: 0.440 AC: 191 AN: 434 Hom.: 35 AF XY: 0.439 AC XY: 116 AN XY: 264

African (AFR) AF: 0.500 AC: 1 AN: 2

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.433 AC: 175 AN: 404

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.500 AC: 12 AN: 24

Other (OTH) AF: 0.750 AC: 3 AN: 4

GnomAD4 genome AF: 0.582 AC: 88521 AN: 152016 Hom.: 26638 Cov.: 32 AF XY: 0.577 AC XY: 42856 AN XY: 74302

African (AFR) AF: 0.722 AC: 29935 AN: 41456

American (AMR) AF: 0.660 AC: 10084 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.545 AC: 1889 AN: 3466

East Asian (EAS) AF: 0.587 AC: 3027 AN: 5160

South Asian (SAS) AF: 0.368 AC: 1772 AN: 4814

European-Finnish (FIN) AF: 0.444 AC: 4701 AN: 10576

Middle Eastern (MID) AF: 0.521 AC: 152 AN: 292

European-Non Finnish (NFE) AF: 0.518 AC: 35221 AN: 67944

Other (OTH) AF: 0.565 AC: 1195 AN: 2114

Alfa AF: 0.530 Hom.: 22454

Bravo AF: 0.608

Asia WGS AF: 0.536 AC: 1863 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.7
DANN	Benign	0.67
PhyloP100		-0.70
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: rs137487; hg19: chr22-33259104;