NM_000362.5:c.261C>T

Variant names:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

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 (★★).

Frequency

Genomes: 𝑓 0.088 ( 908 hom., cov: 32)

Exomes 𝑓: 0.087 ( 8304 hom. )

Consequence

TIMP3
NM_000362.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -5.11

Variant links:

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]

TIMP3 links:

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]

SYN3 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 341343.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr22-32857305-C-T is described in Lovd as [Likely_benign].

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 link	c.261C>T	p.Ser87Ser	synonymous_variant	Exon 3 of 5	ENST00000266085.7	NP_000353.1	P35625
SYN3	NM_003490.4 link	c.711+7610G>A		intron_variant	Intron 6 of 13	ENST00000358763.7	NP_003481.3	O14994A0A024R1I8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TIMP3	ENST00000266085.7 link	c.261C>T	p.Ser87Ser	synonymous_variant	Exon 3 of 5	1	NM_000362.5	ENSP00000266085.5	P35625
SYN3	ENST00000358763.7 link	c.711+7610G>A		intron_variant	Intron 6 of 13	5	NM_003490.4	ENSP00000351614.2	O14994
SYN3	ENST00000462268.1 link	n.225+7610G>A		intron_variant	Intron 2 of 2	3

Frequencies

GnomAD3 genomes

AF:

0.0881

AC:

13385

AN:

152000

Hom.:

906

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.113

AC:

28289

AN:

251368

Hom.:

2804

AF XY:

0.103

AC XY:

13974

AN XY:

135848

show subpopulations

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 SAS exome

AF:

0.0584

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.:

AF XY:

0.0849

AC XY:

61728

AN XY:

726742

show subpopulations

Gnomad4 AFR exome

AF:

0.0555

Gnomad4 AMR exome

AF:

0.255

Gnomad4 ASJ exome

AF:

0.0385

Gnomad4 EAS exome

AF:

0.363

Gnomad4 SAS exome

AF:

0.0570

Gnomad4 FIN exome

AF:

0.0482

Gnomad4 NFE exome

AF:

0.0770

Gnomad4 OTH exome

AF:

0.0855

GnomAD4 genome

AF:

0.0880

AC:

13386

AN:

152118

Hom.:

908

Cov.:

AF XY:

0.0900

AC XY:

6693

AN XY:

74372

show subpopulations

Gnomad4 AFR

AF:

0.0615

Gnomad4 AMR

AF:

0.193

Gnomad4 ASJ

AF:

0.0378

Gnomad4 EAS

AF:

0.347

Gnomad4 SAS

AF:

0.0708

Gnomad4 FIN

AF:

0.0495

Gnomad4 NFE

AF:

0.0712

Gnomad4 OTH

AF:

0.0833

Alfa

AF:

0.0741

Hom.:

1002

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

LINK: link

Submissions by phenotype

not provided

Benign:3

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) -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over