rs2234921

Variant names:

• chr22-32801088-A-G
• rs2234921
• NM_003490.4:c.711+63827T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_003490.4(SYN3):​c.711+63827T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.381 in 152,090 control chromosomes in the GnomAD database, including 12,542 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.38 (12542 hom., cov: 32)
• Consequence: SYN3 NM_003490.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.831
• Publications: 10 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]

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 22-32801088-A-G is Benign according to our data. Variant chr22-32801088-A-G is described in ClinVar as Benign. ClinVar VariationId is 341328.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.587 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYN3	NM_003490.4	c.711+63827T>C		intron_variant	Intron 6 of 13	ENST00000358763.7	NP_003481.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYN3	ENST00000358763.7	c.711+63827T>C		intron_variant	Intron 6 of 13	5	NM_003490.4	ENSP00000351614.2
SYN3	ENST00000462268.1	n.225+63827T>C		intron_variant	Intron 2 of 2	3

Frequencies

GnomAD3 genomes AF: 0.381 AC: 57905 AN: 151972 Hom.: 12505 Cov.: 32

Gnomad AFR AF: 0.593

Gnomad AMI AF: 0.193

Gnomad AMR AF: 0.358

Gnomad ASJ AF: 0.374

Gnomad EAS AF: 0.0913

Gnomad SAS AF: 0.210

Gnomad FIN AF: 0.278

Gnomad MID AF: 0.443

Gnomad NFE AF: 0.310

Gnomad OTH AF: 0.393

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

GnomAD4 genome AF: 0.381 AC: 58002 AN: 152090 Hom.: 12542 Cov.: 32 AF XY: 0.374 AC XY: 27816 AN XY: 74348

African (AFR) AF: 0.593 AC: 24608 AN: 41470

American (AMR) AF: 0.358 AC: 5485 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.374 AC: 1296 AN: 3468

East Asian (EAS) AF: 0.0915 AC: 474 AN: 5182

South Asian (SAS) AF: 0.209 AC: 1008 AN: 4824

European-Finnish (FIN) AF: 0.278 AC: 2935 AN: 10564

Middle Eastern (MID) AF: 0.452 AC: 133 AN: 294

European-Non Finnish (NFE) AF: 0.310 AC: 21064 AN: 67962

Other (OTH) AF: 0.390 AC: 823 AN: 2112

Alfa AF: 0.372 Hom.: 2594

Bravo AF: 0.401

Asia WGS AF: 0.191 AC: 667 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Sorsby fundus dystrophy Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.94
DANN	Benign	0.56
PhyloP100		-0.83
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: rs2234921; hg19: chr22-33197074;