22-32857293-T-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000362.5(TIMP3):c.249T>C(p.His83His) variant causes a synonymous change. The variant allele was found at a frequency of 0.525 in 1,612,676 control chromosomes in the GnomAD database, including 228,674 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.61 ( 29994 hom., cov: 31)

Exomes 𝑓: 0.52 ( 198680 hom. )

Consequence

TIMP3
NM_000362.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 4.55

Publications

60 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.6).

BP6

Variant 22-32857293-T-C is Benign according to our data. Variant chr22-32857293-T-C is described in ClinVar as Benign. ClinVar VariationId is 255943.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.828 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000362.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TIMP3	NM_000362.5	MANE Select	c.249T>C	p.His83His	synonymous	Exon 3 of 5	NP_000353.1	P35625
SYN3	NM_003490.4	MANE Select	c.711+7622A>G		intron	N/A	NP_003481.3
SYN3	NM_001369907.1		c.711+7622A>G		intron	N/A	NP_001356836.1	O14994

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TIMP3	ENST00000266085.7	TSL:1 MANE Select	c.249T>C	p.His83His	synonymous	Exon 3 of 5	ENSP00000266085.5	P35625
SYN3	ENST00000358763.7	TSL:5 MANE Select	c.711+7622A>G		intron	N/A	ENSP00000351614.2	O14994
TIMP3	ENST00000908983.1		c.366T>C	p.His122His	synonymous	Exon 4 of 6	ENSP00000579042.1

Frequencies

GnomAD3 genomes

AF:

0.609

AC:

92549

AN:

151848

Hom.:

29934

Cov.:

show subpopulations

Gnomad AFR

AF:

0.835

Gnomad AMI

AF:

0.715

Gnomad AMR

AF:

0.664

Gnomad ASJ

AF:

0.536

Gnomad EAS

AF:

0.609

Gnomad SAS

AF:

0.535

Gnomad FIN

AF:

0.438

Gnomad MID

AF:

0.576

Gnomad NFE

AF:

0.495

Gnomad OTH

AF:

0.594

GnomAD2 exomes

AF:

0.553

AC:

139046

AN:

251376

AF XY:

0.541

show subpopulations

Gnomad AFR exome

AF:

0.834

Gnomad AMR exome

AF:

0.707

Gnomad ASJ exome

AF:

0.549

Gnomad EAS exome

AF:

0.583

Gnomad FIN exome

AF:

0.429

Gnomad NFE exome

AF:

0.491

Gnomad OTH exome

AF:

0.535

GnomAD4 exome

AF:

0.516

AC:

753378

AN:

1460710

Hom.:

198680

Cov.:

AF XY:

0.514

AC XY:

373521

AN XY:

726704

show subpopulations

African (AFR)

AF:

0.845

AC:

28270

AN:

33472

American (AMR)

AF:

0.703

AC:

31449

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.549

AC:

14340

AN:

26130

East Asian (EAS)

AF:

0.643

AC:

25527

AN:

39684

South Asian (SAS)

AF:

0.535

AC:

46167

AN:

86240

European-Finnish (FIN)

AF:

0.429

AC:

22928

AN:

53408

Middle Eastern (MID)

AF:

0.576

AC:

3320

AN:

5764

European-Non Finnish (NFE)

AF:

0.494

AC:

548940

AN:

1110950

Other (OTH)

AF:

0.538

AC:

32437

AN:

60338

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

19296

38591

57887

77182

96478

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16300

32600

48900

65200

81500

<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:

0.610

AC:

92670

AN:

151966

Hom.:

29994

Cov.:

AF XY:

0.607

AC XY:

45041

AN XY:

74258

show subpopulations

African (AFR)

AF:

0.835

AC:

34660

AN:

41488

American (AMR)

AF:

0.665

AC:

10156

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.536

AC:

1860

AN:

3472

East Asian (EAS)

AF:

0.609

AC:

3136

AN:

5146

South Asian (SAS)

AF:

0.534

AC:

2552

AN:

4782

European-Finnish (FIN)

AF:

0.438

AC:

4614

AN:

10544

Middle Eastern (MID)

AF:

0.588

AC:

173

AN:

294

European-Non Finnish (NFE)

AF:

0.495

AC:

33622

AN:

67948

Other (OTH)

AF:

0.591

AC:

1246

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1718

3436

5154

6872

8590

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

748

1496

2244

2992

3740

<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:

0.535

Hom.:

44604

Bravo

AF:

0.638

Asia WGS

AF:

0.621

AC:

2157

AN:

3478

EpiCase

AF:

0.498

EpiControl

AF:

0.503

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Sorsby fundus dystrophy (2)

Fundus dystrophy, pseudoinflammatory, recessive form (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.60

CADD

Benign

(source)

DANN

Benign

0.89

PhyloP100

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=75/25

polymorphism (auto)

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over