rs1270675463

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_000362.5(TIMP3):c.113C>G(p.Ser38Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000253 in 1,582,802 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

TIMP3
NM_000362.5 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3

Conservation

PhyloP100: 4.73

Publications

13 publications found

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 was made for transcript

Our verdict: Pathogenic. The variant received 16 ACMG points.

PM1

In a chain Metalloproteinase inhibitor 3 (size 187) in uniprot entity TIMP3_HUMAN there are 12 pathogenic changes around while only 4 benign (75%) in NM_000362.5

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.972

PP5

Variant 22-32802114-C-G is Pathogenic according to our data. Variant chr22-32802114-C-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 843268.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TIMP3	NM_000362.5 link	c.113C>G	p.Ser38Cys	missense_variant	Exon 1 of 5	ENST00000266085.7	NP_000353.1	P35625
SYN3	NM_003490.4 link	c.711+62801G>C		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.113C>G	p.Ser38Cys	missense_variant	Exon 1 of 5	1	NM_000362.5	ENSP00000266085.5	P35625
SYN3	ENST00000358763.7 link	c.711+62801G>C		intron_variant	Intron 6 of 13	5	NM_003490.4	ENSP00000351614.2	O14994
SYN3	ENST00000462268.1 link	n.225+62801G>C		intron_variant	Intron 2 of 2	3

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000210

AC:

AN:

1430622

Hom.:

Cov.:

AF XY:

0.00000282

AC XY:

AN XY:

709950

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33098

American (AMR)

AF:

0.00

AC:

AN:

41736

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25654

East Asian (EAS)

AF:

0.00

AC:

AN:

38600

South Asian (SAS)

AF:

0.00

AC:

AN:

82580

European-Finnish (FIN)

AF:

0.00

AC:

AN:

41600

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5742

European-Non Finnish (NFE)

AF:

0.00000272

AC:

AN:

1102158

Other (OTH)

AF:

0.00

AC:

AN:

59454

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152180

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74332

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41456

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5156

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:2

Sep 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces serine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 38 of the TIMP3 protein (p.Ser38Cys). This variant is present in population databases (no rsID available, gnomAD 0.007%). This missense change has been observed in individuals with clinical features of Sorsby fundus dystrophy (SFD) (PMID: 23023527, 26493035, 27601084, 28559085). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 843268). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic. -

Feb 08, 2019

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Haplotype analysis suggests that S38C is a founder variant in individuals of Western-European background (Naessens et al., 2019); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; A published functional study suggests that the S38C variant creates a new disulfide bond at Cys36-Cys38 and disrupts the wild type Cys36-Cys143 disulfide bond, although the disease mechanism for TIMP3 has not been fully established (Naessens et al., 2019); This variant is associated with the following publications: (PMID: 31369189, 10873973, 30668888, 27601084, 25082885, 23023527, 23662816, 28847738, 30129971, 29125146, 28559085, 26493035) -

Retinal dystrophy

Pathogenic:1

Feb 28, 2019

Blueprint Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.88

BayesDel_addAF

Pathogenic

0.49

BayesDel_noAF

Pathogenic

0.47

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.96

Eigen

Pathogenic

0.79

Eigen_PC

Pathogenic

0.74

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.86

M_CAP

Pathogenic

0.51

MetaRNN

Pathogenic

0.97

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

3.0

PhyloP100

4.7

PrimateAI

Pathogenic

0.85

PROVEAN

Uncertain

-2.9

REVEL

Pathogenic

0.92

Sift

Uncertain

0.015

Sift4G

Uncertain

0.0040

Polyphen

1.0

Vest4

0.95

MutPred

0.84

Loss of catalytic residue at S38 (P = 0.0016);

MVP

1.0

MPC

2.2

ClinPred

0.99

GERP RS

5.3

PromoterAI

-0.041

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.94

gMVP

0.98

Mutation Taster

=19/81

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over