rs137485

chr22-32858296-T-Achr22-32858296-T-Cchr22-32858296-T-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_003490.4(SYN3):c.711+6619A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.771 in 152,076 control chromosomes in the GnomAD database, including 45,720 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.77 (45720 hom., cov: 31)
• Consequence: SYN3 NM_003490.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0830

Genes affected

TIMP3 (HGNC:11822): (TIMP metallopeptidase inhibitor 3) This gene belongs to the TIMP gene family. The proteins encoded by this gene family are inhibitors of the matrix metalloproteinases, a group of peptidases involved in degradation of the extracellular matrix (ECM). Expression of this gene is induced in response to mitogenic stimulation and this netrin domain-containing protein is localized to the ECM. Mutations in this gene have been associated with the autosomal dominant disorder Sorsby's fundus dystrophy. [provided by RefSeq, Jul 2008]

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 22-32858296-T-A is Benign according to our data. Variant chr22-32858296-T-A is described in ClinVar as [Benign]. Clinvar id is 1265243.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.868 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TIMP3	NM_000362.5	c.438+158T>A		intron_variant		ENST00000266085.7
SYN3	NM_003490.4	c.711+6619A>T		intron_variant		ENST00000358763.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TIMP3	ENST00000266085.7	c.438+158T>A		intron_variant		1	NM_000362.5	P1
SYN3	ENST00000358763.7	c.711+6619A>T		intron_variant		5	NM_003490.4	P1
SYN3	ENST00000462268.1	n.225+6619A>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.771 AC: 117176 AN: 151958 Hom.: 45673 Cov.: 31

Gnomad AFR AF: 0.875

Gnomad AMI AF: 0.777

Gnomad AMR AF: 0.814

Gnomad ASJ AF: 0.721

Gnomad EAS AF: 0.874

Gnomad SAS AF: 0.790

Gnomad FIN AF: 0.684

Gnomad MID AF: 0.782

Gnomad NFE AF: 0.705

Gnomad OTH AF: 0.762

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.771 AC: 117287 AN: 152076 Hom.: 45720 Cov.: 31 AF XY: 0.772 AC XY: 57404 AN XY: 74326

Gnomad4 AFR AF: 0.875

Gnomad4 AMR AF: 0.815

Gnomad4 ASJ AF: 0.721

Gnomad4 EAS AF: 0.874

Gnomad4 SAS AF: 0.789

Gnomad4 FIN AF: 0.684

Gnomad4 NFE AF: 0.705

Gnomad4 OTH AF: 0.764

Alfa AF: 0.743 Hom.: 5258

Bravo AF: 0.786

Asia WGS AF: 0.860 AC: 2992 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 12, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
Cadd	Benign	4.6
Dann	Benign	0.79

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

Publications

LitVar

Other links and lift over

dbSNP: rs137485; hg19: chr22-33254283;