rs137485

Variant names:

• chr22-32858296-T-A
• rs137485
• NM_003490.4:c.711+6619A>T

Your query was ambiguous. Multiple possible variants found:

• chr22-32858296-T-A
• chr22-32858296-T-C
• chr22-32858296-T-G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 8 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]

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]

TIMP3 Gene-Disease associations (from GenCC):

• Sorsby fundus dystrophy

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, ClinGen, G2P

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
SYN3	NM_003490.4	c.711+6619A>T		intron_variant	Intron 6 of 13	ENST00000358763.7	NP_003481.3
TIMP3	NM_000362.5	c.438+158T>A		intron_variant	Intron 4 of 4	ENST00000266085.7	NP_000353.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYN3	ENST00000358763.7	c.711+6619A>T		intron_variant	Intron 6 of 13	5	NM_003490.4	ENSP00000351614.2
TIMP3	ENST00000266085.7	c.438+158T>A		intron_variant	Intron 4 of 4	1	NM_000362.5	ENSP00000266085.5
SYN3	ENST00000462268.1	n.225+6619A>T		intron_variant	Intron 2 of 2	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

African (AFR) AF: 0.875 AC: 36345 AN: 41526

American (AMR) AF: 0.815 AC: 12455 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.721 AC: 2501 AN: 3470

East Asian (EAS) AF: 0.874 AC: 4496 AN: 5142

South Asian (SAS) AF: 0.789 AC: 3801 AN: 4818

European-Finnish (FIN) AF: 0.684 AC: 7236 AN: 10580

Middle Eastern (MID) AF: 0.799 AC: 235 AN: 294

European-Non Finnish (NFE) AF: 0.705 AC: 47901 AN: 67942

Other (OTH) AF: 0.764 AC: 1608 AN: 2104

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

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	4.6
DANN	Benign	0.79
PhyloP100		0.083
Mutation Taster		=100/0	polymorphism (auto)

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: rs137485; hg19: chr22-33254283;