rs28897669

Variant names:

• chr3-12155799-G-A
• rs28897669
• NM_133625.6:c.774+4473G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_133625.6(SYN2):​c.774+4473G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0794 in 152,160 control chromosomes in the GnomAD database, including 579 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 0.079 (579 hom., cov: 32)
• Consequence: SYN2 NM_133625.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.242
• Publications: 0 publications found

Genes affected

SYN2 (HGNC:11495): (synapsin II) 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. This member of the synapsin family encodes a neuron-specific phosphoprotein that selectively binds to small synaptic vesicles in the presynaptic nerve terminal. Polymorphisms in this gene are associated with abnormal presynaptic function and related neuronal disorders, including autism, epilepsy, bipolar disorder and schizophrenia. Alternative splicing of this gene results in multiple transcript variants. The tissue inhibitor of metalloproteinase 4 gene is located within an intron of this gene and is transcribed in the opposite direction. [provided by RefSeq, Feb 2014]

TIMP4 (HGNC:11823): (TIMP metallopeptidase inhibitor 4) 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. The secreted, netrin domain-containing protein encoded by this gene is involved in regulation of platelet aggregation and recruitment and may play role in hormonal regulation and endometrial tissue remodeling. [provided by RefSeq, Jul 2008]

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 (AFR) allele frequency at 95% confidence interval = 0.125 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_133625.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYN2	NM_133625.6	MANE Select	c.774+4473G>A		intron	N/A	NP_598328.1
	TIMP4	NM_003256.4	MANE Select	c.352+1021C>T		intron	N/A	NP_003247.1
	SYN2	NM_003178.6		c.774+4473G>A		intron	N/A	NP_003169.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYN2	ENST00000621198.5	TSL:1 MANE Select	c.774+4473G>A		intron	N/A	ENSP00000480050.1
	TIMP4	ENST00000287814.5	TSL:1 MANE Select	c.352+1021C>T		intron	N/A	ENSP00000287814.4
	SYN2	ENST00000620175.4	TSL:1	c.774+4473G>A		intron	N/A	ENSP00000484916.1

Frequencies

GnomAD3 genomes AF: 0.0793 AC: 12064 AN: 152042 Hom.: 576 Cov.: 32

Gnomad AFR AF: 0.128

Gnomad AMI AF: 0.00220

Gnomad AMR AF: 0.0800

Gnomad ASJ AF: 0.136

Gnomad EAS AF: 0.0932

Gnomad SAS AF: 0.0726

Gnomad FIN AF: 0.0434

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.0529

Gnomad OTH AF: 0.0784

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

GnomAD4 genome AF: 0.0794 AC: 12078 AN: 152160 Hom.: 579 Cov.: 32 AF XY: 0.0802 AC XY: 5966 AN XY: 74382

African (AFR) AF: 0.127 AC: 5289 AN: 41504

American (AMR) AF: 0.0799 AC: 1221 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.136 AC: 471 AN: 3470

East Asian (EAS) AF: 0.0934 AC: 483 AN: 5170

South Asian (SAS) AF: 0.0735 AC: 354 AN: 4816

European-Finnish (FIN) AF: 0.0434 AC: 460 AN: 10600

Middle Eastern (MID) AF: 0.105 AC: 31 AN: 294

European-Non Finnish (NFE) AF: 0.0529 AC: 3600 AN: 67992

Other (OTH) AF: 0.0790 AC: 167 AN: 2114

Alfa AF: 0.0670 Hom.: 59

Bravo AF: 0.0832

Asia WGS AF: 0.113 AC: 394 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	3.3
DANN	Benign	0.41
PhyloP100		0.24
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: rs28897669; hg19: chr3-12197299;