rs738992

Variant names:

• chr22-32814019-C-T
• rs738992
• NM_003490.4:c.711+50896G>A

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+50896G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.441 in 151,138 control chromosomes in the GnomAD database, including 15,380 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 0.44 (15380 hom., cov: 28)
• Consequence: SYN3 NM_003490.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0180
• Publications: 9 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

LOC124905104 (HGNC:):

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 (AMR) allele frequency at 95% confidence interval = 0.54 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYN3	NM_003490.4	c.711+50896G>A		intron_variant	Intron 6 of 13	ENST00000358763.7	NP_003481.3
TIMP3	NM_000362.5	c.121+11897C>T		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+50896G>A		intron_variant	Intron 6 of 13	5	NM_003490.4	ENSP00000351614.2
TIMP3	ENST00000266085.7	c.121+11897C>T		intron_variant	Intron 1 of 4	1	NM_000362.5	ENSP00000266085.5
SYN3	ENST00000462268.1	n.225+50896G>A		intron_variant	Intron 2 of 2	3

Frequencies

GnomAD3 genomes AF: 0.441 AC: 66649 AN: 151018 Hom.: 15380 Cov.: 28

Gnomad AFR AF: 0.307

Gnomad AMI AF: 0.545

Gnomad AMR AF: 0.550

Gnomad ASJ AF: 0.433

Gnomad EAS AF: 0.529

Gnomad SAS AF: 0.347

Gnomad FIN AF: 0.513

Gnomad MID AF: 0.484

Gnomad NFE AF: 0.486

Gnomad OTH AF: 0.455

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

GnomAD4 genome AF: 0.441 AC: 66665 AN: 151138 Hom.: 15380 Cov.: 28 AF XY: 0.443 AC XY: 32640 AN XY: 73710

African (AFR) AF: 0.307 AC: 12620 AN: 41128

American (AMR) AF: 0.550 AC: 8330 AN: 15150

Ashkenazi Jewish (ASJ) AF: 0.433 AC: 1500 AN: 3468

East Asian (EAS) AF: 0.529 AC: 2694 AN: 5094

South Asian (SAS) AF: 0.346 AC: 1652 AN: 4770

European-Finnish (FIN) AF: 0.513 AC: 5339 AN: 10402

Middle Eastern (MID) AF: 0.479 AC: 140 AN: 292

European-Non Finnish (NFE) AF: 0.486 AC: 32950 AN: 67838

Other (OTH) AF: 0.453 AC: 946 AN: 2090

Alfa AF: 0.480 Hom.: 68248

Bravo AF: 0.442

Asia WGS AF: 0.448 AC: 1553 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	3.3
DANN	Benign	0.67
PhyloP100		0.018
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
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: rs738992; hg19: chr22-33210005;