Genetic Variant SYN3:p.Glu525Lys (chr22-32518080-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_003490.4(SYN3):c.1573G>A(p.Glu525Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E525Q) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Consequence

SYN3
NM_003490.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.700

Publications

5 publications found

Variant links:

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]

SYN3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.05418709).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003490.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SYN3	NM_003490.4	MANE Select	c.1573G>A	p.Glu525Lys	missense	Exon 13 of 14	NP_003481.3
SYN3	NM_001369907.1		c.1573G>A	p.Glu525Lys	missense	Exon 13 of 14	NP_001356836.1	O14994
SYN3	NM_001369908.1		c.1573G>A	p.Glu525Lys	missense	Exon 13 of 14	NP_001356837.1	O14994

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SYN3	ENST00000358763.7	TSL:5 MANE Select	c.1573G>A	p.Glu525Lys	missense	Exon 13 of 14	ENSP00000351614.2	O14994
SYN3	ENST00000459990.5	TSL:4	n.546G>A		non_coding_transcript_exon	Exon 3 of 3
SYN3	ENST00000461446.1	TSL:2	n.464G>A		non_coding_transcript_exon	Exon 2 of 3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

189188

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.062

Eigen

Benign

-0.58

Eigen_PC

Benign

-0.42

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.82

M_CAP

Benign

0.0068

MetaRNN

Benign

0.054

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.4

PhyloP100

0.70

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.27

REVEL

Benign

0.068

Sift

Benign

0.67

Sift4G

Benign

0.85

Polyphen

0.039

Vest4

0.19

MutPred

0.29

Gain of MoRF binding (P = 0.0055)

MVP

0.31

MPC

0.72

ClinPred

0.60

GERP RS

4.9

Varity_R

0.052

gMVP

0.16

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over