Genetic Variant SYN3:p.Arg435Gly (chr22-32527933-G-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_003490.4(SYN3):c.1303C>G(p.Arg435Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000000696 in 1,436,794 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. R435C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

SYN3
NM_003490.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.08

Publications

0 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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2558088).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYN3	NM_003490.4 link	c.1303C>G	p.Arg435Gly	missense_variant	Exon 12 of 14	ENST00000358763.7	NP_003481.3	O14994A0A024R1I8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYN3	ENST00000358763.7 link	c.1303C>G	p.Arg435Gly	missense_variant	Exon 12 of 14	5	NM_003490.4	ENSP00000351614.2		O14994

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.96e-7

AC:

AN:

1436794

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

712634

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32866

American (AMR)

AF:

0.00

AC:

AN:

42212

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25620

East Asian (EAS)

AF:

0.00

AC:

AN:

38388

South Asian (SAS)

AF:

0.00

AC:

AN:

82862

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51344

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5744

European-Non Finnish (NFE)

AF:

9.10e-7

AC:

AN:

1098494

Other (OTH)

AF:

0.00

AC:

AN:

59264

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.35

BayesDel_addAF

Benign

-0.022

BayesDel_noAF

Benign

-0.27

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.59

D;T;T

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Benign

0.67

LIST_S2

Benign

0.84

T;T;T

M_CAP

Benign

0.023

MetaRNN

Benign

0.26

T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Uncertain

2.4

M;.;.

PhyloP100

4.1

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-2.3

N;D;.

REVEL

Benign

0.12

Sift

Benign

0.084

T;D;.

Sift4G

Benign

0.21

T;T;T

Polyphen

0.98

D;.;.

Vest4

0.59

MutPred

0.32

Gain of relative solvent accessibility (P = 0.0098);.;.;

MVP

0.26

MPC

0.25

ClinPred

0.93

GERP RS

3.6

Varity_R

0.13

gMVP

0.31

Mutation Taster

=76/24

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over