rs242077

Positions:

• chr22-32833699-T-C

Variant summary

Our verdict is Benign. Variant got -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

Genes affected

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]

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]

ACMG classification

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TIMP3	NM_000362.5	c.122-15753T>C		intron_variant		ENST00000266085.7
SYN3	NM_003490.4	c.711+31216A>G		intron_variant		ENST00000358763.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TIMP3	ENST00000266085.7	c.122-15753T>C		intron_variant		1	NM_000362.5	P1
SYN3	ENST00000358763.7	c.711+31216A>G		intron_variant		5	NM_003490.4	P1
SYN3	ENST00000462268.1	n.225+31216A>G		intron_variant, non_coding_transcript_variant		3

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

Gnomad4 AFR exome AF: 0.529

Gnomad4 AMR exome AF: 0.700

Gnomad4 ASJ exome AF: 0.609

Gnomad4 EAS exome AF: 0.575

Gnomad4 SAS exome AF: 0.475

Gnomad4 FIN exome AF: 0.567

Gnomad4 NFE exome AF: 0.584

Gnomad4 OTH exome AF: 0.580

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

Gnomad4 AFR AF: 0.543

Gnomad4 AMR AF: 0.668

Gnomad4 ASJ AF: 0.626

Gnomad4 EAS AF: 0.588

Gnomad4 SAS AF: 0.495

Gnomad4 FIN AF: 0.588

Gnomad4 NFE AF: 0.593

Gnomad4 OTH AF: 0.602

Alfa AF: 0.598 Hom.: 17261

Bravo AF: 0.592

Asia WGS AF: 0.560 AC: 1944 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.55
DANN	Benign	0.41

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

Publications

LitVar

Other links and lift over

dbSNP: rs242077; hg19: chr22-33229685;