22-32518325-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_003490.4(SYN3):c.1328G>A(p.Arg443His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00619 in 1,607,586 control chromosomes in the GnomAD database, including 35 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0056 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0063 (32 hom.)
• Consequence: SYN3 NM_003490.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.25

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

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006853074).
• BP6: Variant 22-32518325-C-T is Benign according to our data. Variant chr22-32518325-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 785839.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYN3	NM_003490.4	c.1328G>A	p.Arg443His	missense_variant	13/14	ENST00000358763.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYN3	ENST00000358763.7	c.1328G>A	p.Arg443His	missense_variant	13/14	5	NM_003490.4	P1

Frequencies

GnomAD3 genomes AF: 0.00555 AC: 842 AN: 151616 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00143

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00479

Gnomad ASJ AF: 0.0107

Gnomad EAS AF: 0.000387

Gnomad SAS AF: 0.00354

Gnomad FIN AF: 0.00743

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00822

Gnomad OTH AF: 0.00766

GnomAD3 exomes AF: 0.00577 AC: 1401 AN: 242826 Hom.: 6 AF XY: 0.00600 AC XY: 790 AN XY: 131742

Gnomad AFR exome AF: 0.00147

Gnomad AMR exome AF: 0.00272

Gnomad ASJ exome AF: 0.0119

Gnomad EAS exome AF: 0.0000550

Gnomad SAS exome AF: 0.00556

Gnomad FIN exome AF: 0.00687

Gnomad NFE exome AF: 0.00755

Gnomad OTH exome AF: 0.00642

GnomAD4 exome AF: 0.00625 AC: 9102 AN: 1455856 Hom.: 32 Cov.: 31 AF XY: 0.00636 AC XY: 4603 AN XY: 723824

Gnomad4 AFR exome AF: 0.000905

Gnomad4 AMR exome AF: 0.00298

Gnomad4 ASJ exome AF: 0.0112

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00532

Gnomad4 FIN exome AF: 0.00627

Gnomad4 NFE exome AF: 0.00669

Gnomad4 OTH exome AF: 0.00664

GnomAD4 genome AF: 0.00556 AC: 843 AN: 151730 Hom.: 3 Cov.: 32 AF XY: 0.00576 AC XY: 427 AN XY: 74114

Gnomad4 AFR AF: 0.00143

Gnomad4 AMR AF: 0.00479

Gnomad4 ASJ AF: 0.0107

Gnomad4 EAS AF: 0.000388

Gnomad4 SAS AF: 0.00376

Gnomad4 FIN AF: 0.00743

Gnomad4 NFE AF: 0.00822

Gnomad4 OTH AF: 0.00758

Alfa AF: 0.00868 Hom.: 2

Bravo AF: 0.00487

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00519 AC: 20

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.00837 AC: 72

ExAC AF: 0.00589 AC: 715

Asia WGS AF: 0.00231 AC: 8 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	SYN3: BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.28
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.14	T;T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Benign	0.0087	T
MetaRNN	Benign	0.0069	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.0	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.5	N;.
REVEL	Benign	0.094
Sift	Benign	0.073	T;.
Sift4G	Benign	0.12	T;T
Polyphen		1.0	D;.
Vest4		0.52
MVP		0.32
MPC		0.24
ClinPred		0.0091	T
GERP RS		4.6
Varity_R		0.13
gMVP		0.15

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

LitVar

Other links and lift over

dbSNP: rs150768274; hg19: chr22-32914312; COSMIC: COSV105903883;