rs743751

Variant names:

• chr22-32838192-C-G
• rs743751
• NM_003490.4:c.711+26723G>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+26723G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.104 in 152,232 control chromosomes in the GnomAD database, including 973 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 (973 hom., cov: 32)
• Consequence: SYN3 NM_003490.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.443
• Publications: 6 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=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.17 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYN3	NM_003490.4	c.711+26723G>C		intron_variant	Intron 6 of 13	ENST00000358763.7	NP_003481.3
TIMP3	NM_000362.5	c.122-11260C>G		intron_variant	Intron 1 of 4	ENST00000266085.7	NP_000353.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYN3	ENST00000358763.7	c.711+26723G>C		intron_variant	Intron 6 of 13	5	NM_003490.4	ENSP00000351614.2
TIMP3	ENST00000266085.7	c.122-11260C>G		intron_variant	Intron 1 of 4	1	NM_000362.5	ENSP00000266085.5
SYN3	ENST00000462268.1	n.225+26723G>C		intron_variant	Intron 2 of 2	3

Frequencies

GnomAD3 genomes AF: 0.104 AC: 15880 AN: 152114 Hom.: 971 Cov.: 32

Gnomad AFR AF: 0.173

Gnomad AMI AF: 0.0681

Gnomad AMR AF: 0.0768

Gnomad ASJ AF: 0.114

Gnomad EAS AF: 0.0531

Gnomad SAS AF: 0.0723

Gnomad FIN AF: 0.0834

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.0783

Gnomad OTH AF: 0.100

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

GnomAD4 genome AF: 0.104 AC: 15900 AN: 152232 Hom.: 973 Cov.: 32 AF XY: 0.104 AC XY: 7728 AN XY: 74422

African (AFR) AF: 0.173 AC: 7182 AN: 41512

American (AMR) AF: 0.0765 AC: 1171 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.114 AC: 395 AN: 3468

East Asian (EAS) AF: 0.0532 AC: 276 AN: 5184

South Asian (SAS) AF: 0.0719 AC: 347 AN: 4826

European-Finnish (FIN) AF: 0.0834 AC: 884 AN: 10604

Middle Eastern (MID) AF: 0.147 AC: 43 AN: 292

European-Non Finnish (NFE) AF: 0.0783 AC: 5327 AN: 68022

Other (OTH) AF: 0.101 AC: 213 AN: 2112

Alfa AF: 0.0922 Hom.: 104

Bravo AF: 0.109

Asia WGS AF: 0.0610 AC: 214 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.93
DANN	Benign	0.61
PhyloP100		-0.44
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: rs743751; hg19: chr22-33234179;