22-32518106-C-T

Variant names:

• chr22-32518106-C-T
• rs574127377
• NM_003490.4:c.1547G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003490.4(SYN3):​c.1547G>A​(p.Gly516Asp) variant causes a missense change. The variant allele was found at a frequency of 0.000000698 in 1,432,426 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. G516V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: SYN3 NM_003490.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.43
• Publications: 0 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21417391).

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.1547G>A	p.Gly516Asp	missense	Exon 13 of 14	NP_003481.3
	SYN3	NM_001369907.1		c.1547G>A	p.Gly516Asp	missense	Exon 13 of 14	NP_001356836.1	O14994
	SYN3	NM_001369908.1		c.1547G>A	p.Gly516Asp	missense	Exon 13 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.1547G>A	p.Gly516Asp	missense	Exon 13 of 14	ENSP00000351614.2	O14994
	SYN3	ENST00000459990.5	TSL:4	n.520G>A		non_coding_transcript_exon	Exon 3 of 3
	SYN3	ENST00000461446.1	TSL:2	n.438G>A		non_coding_transcript_exon	Exon 2 of 3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000444 AC: 1 AN: 225086 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: 0.00000977

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.98e-7 AC: 1 AN: 1432426 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 709874

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

American (AMR) AF: 0.00 AC: 0 AN: 40862

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23854

East Asian (EAS) AF: 0.00 AC: 0 AN: 39476

South Asian (SAS) AF: 0.00 AC: 0 AN: 80460

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52290

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5574

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1098066

Other (OTH) AF: 0.0000169 AC: 1 AN: 59142

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.069	T
BayesDel_noAF	Benign	-0.34
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		5.4
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.079
Sift	Benign	0.096	T
Sift4G	Uncertain	0.049	D
Polyphen		0.75	P
Vest4		0.48
MutPred		0.28		Loss of MoRF binding (P = 0.0491)
MVP		0.16
MPC		0.86
ClinPred		0.64	D
GERP RS		4.9
Varity_R		0.14
gMVP		0.22
Mutation Taster		=64/36	polymorphism

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: rs574127377; hg19: chr22-32914093;