rs483352708

Variant names:

• chr22-32527986-G-A
• rs483352708
• NM_003490.4:c.1250C>T

Your query was ambiguous. Multiple possible variants found:

• chr22-32527986-G-A
• chr22-32527986-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_003490.4(SYN3):​c.1250C>T​(p.Ala417Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000189 in 1,585,158 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/24 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SYN3 NM_003490.4 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:2
• Conservation: PhyloP100: 1.14
• Publications: 1 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYN3	NM_003490.4	MANE Select	c.1250C>T	p.Ala417Val	missense	Exon 12 of 14	NP_003481.3
	SYN3	NM_001369907.1		c.1250C>T	p.Ala417Val	missense	Exon 12 of 14	NP_001356836.1	O14994
	SYN3	NM_001369908.1		c.1250C>T	p.Ala417Val	missense	Exon 12 of 14	NP_001356837.1	O14994

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYN3	ENST00000358763.7	TSL:5 MANE Select	c.1250C>T	p.Ala417Val	missense	Exon 12 of 14	ENSP00000351614.2	O14994
	SYN3	ENST00000468922.1	TSL:3	n.297C>T		non_coding_transcript_exon	Exon 3 of 4
	SYN3	ENST00000483062.5	TSL:3	n.218C>T		non_coding_transcript_exon	Exon 2 of 4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152212 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000140 AC: 2 AN: 1432946 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 710386

African (AFR) AF: 0.00 AC: 0 AN: 32702

American (AMR) AF: 0.0000241 AC: 1 AN: 41428

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25498

East Asian (EAS) AF: 0.00 AC: 0 AN: 38316

South Asian (SAS) AF: 0.00 AC: 0 AN: 82288

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51486

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5706

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1096384

Other (OTH) AF: 0.0000169 AC: 1 AN: 59138

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152212 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74356

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41452

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2092

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	20
DANN	Benign	0.87
DEOGEN2	Benign	0.084	T
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.0058	T
MetaRNN	Benign	0.099	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.49	N
PhyloP100		1.1
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.14	N
REVEL	Benign	0.035
Sift	Benign	0.16	T
Sift4G	Benign	0.24	T
Polyphen		0.0020	B
Vest4		0.10
MutPred		0.16		Gain of methylation at K418 (P = 0.0354)
MVP		0.24
MPC		0.19
ClinPred		0.20	T
GERP RS		1.3
Varity_R		0.029
gMVP		0.12
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.25		Position offset: 19

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

Other links and lift over

dbSNP: rs483352708; hg19: chr22-32923973;