22-32857305-C-T

Variant names:

• chr22-32857305-C-T
• rs11547635
• NM_000362.5:c.261C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000362.5(TIMP3):​c.261C>T​(p.Ser87Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0871 in 1,612,884 control chromosomes in the GnomAD database, including 9,212 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S87S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.088 (908 hom., cov: 32)
  • Exomes 𝑓: 0.087 (8304 hom.)
• Consequence: TIMP3 NM_000362.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -5.11
• Publications: 41 publications found

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

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 22-32857305-C-T is Benign according to our data. Variant chr22-32857305-C-T is described in ClinVar as Benign. ClinVar VariationId is 341343.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-5.11 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.334 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TIMP3	NM_000362.5	c.261C>T	p.Ser87Ser	synonymous_variant	Exon 3 of 5	ENST00000266085.7	NP_000353.1
SYN3	NM_003490.4	c.711+7610G>A		intron_variant	Intron 6 of 13	ENST00000358763.7	NP_003481.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TIMP3	ENST00000266085.7	c.261C>T	p.Ser87Ser	synonymous_variant	Exon 3 of 5	1	NM_000362.5	ENSP00000266085.5
SYN3	ENST00000358763.7	c.711+7610G>A		intron_variant	Intron 6 of 13	5	NM_003490.4	ENSP00000351614.2
SYN3	ENST00000462268.1	n.225+7610G>A		intron_variant	Intron 2 of 2	3

Frequencies

GnomAD3 genomes AF: 0.0881 AC: 13385 AN: 152000 Hom.: 906 Cov.: 32

Gnomad AFR AF: 0.0617

Gnomad AMI AF: 0.0747

Gnomad AMR AF: 0.193

Gnomad ASJ AF: 0.0378

Gnomad EAS AF: 0.347

Gnomad SAS AF: 0.0718

Gnomad FIN AF: 0.0495

Gnomad MID AF: 0.0318

Gnomad NFE AF: 0.0712

Gnomad OTH AF: 0.0832

GnomAD2 exomes AF: 0.113 AC: 28289 AN: 251368 AF XY: 0.103

Gnomad AFR exome AF: 0.0584

Gnomad AMR exome AF: 0.264

Gnomad ASJ exome AF: 0.0395

Gnomad EAS exome AF: 0.334

Gnomad FIN exome AF: 0.0457

Gnomad NFE exome AF: 0.0732

Gnomad OTH exome AF: 0.0912

GnomAD4 exome AF: 0.0870 AC: 127125 AN: 1460766 Hom.: 8304 Cov.: 35 AF XY: 0.0849 AC XY: 61728 AN XY: 726742

African (AFR) AF: 0.0555 AC: 1856 AN: 33468

American (AMR) AF: 0.255 AC: 11407 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0385 AC: 1005 AN: 26128

East Asian (EAS) AF: 0.363 AC: 14407 AN: 39692

South Asian (SAS) AF: 0.0570 AC: 4913 AN: 86240

European-Finnish (FIN) AF: 0.0482 AC: 2575 AN: 53418

Middle Eastern (MID) AF: 0.0390 AC: 225 AN: 5766

European-Non Finnish (NFE) AF: 0.0770 AC: 85576 AN: 1110990

Other (OTH) AF: 0.0855 AC: 5161 AN: 60340

GnomAD4 genome AF: 0.0880 AC: 13386 AN: 152118 Hom.: 908 Cov.: 32 AF XY: 0.0900 AC XY: 6693 AN XY: 74372

African (AFR) AF: 0.0615 AC: 2553 AN: 41506

American (AMR) AF: 0.193 AC: 2956 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0378 AC: 131 AN: 3470

East Asian (EAS) AF: 0.347 AC: 1790 AN: 5152

South Asian (SAS) AF: 0.0708 AC: 339 AN: 4788

European-Finnish (FIN) AF: 0.0495 AC: 525 AN: 10600

Middle Eastern (MID) AF: 0.0342 AC: 10 AN: 292

European-Non Finnish (NFE) AF: 0.0712 AC: 4838 AN: 67996

Other (OTH) AF: 0.0833 AC: 176 AN: 2114

Alfa AF: 0.0759 Hom.: 1205

Bravo AF: 0.0991

Asia WGS AF: 0.234 AC: 812 AN: 3478

EpiCase AF: 0.0666

EpiControl AF: 0.0713

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 30281655)

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Sorsby fundus dystrophy Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	1.3
DANN	Benign	0.82
PhyloP100		-5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=98/2	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: rs11547635; hg19: chr22-33253292; COSMIC: COSV56662276;