Genetic Variant TIMP3:c.-117G>A (chr22-32801885-G-A) – ACMG Classification: Benign (-18 pts)

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBS1BS2

The NM_000362.5(TIMP3):c.-117G>A variant causes a 5 prime UTR change. The variant allele was found at a frequency of 0.00174 in 1,326,686 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0072 ( 10 hom., cov: 32)

Exomes 𝑓: 0.0010 ( 11 hom. )

Consequence

TIMP3
NM_000362.5 5_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 3.68

Publications

2 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 -18 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.46).

BP6

Variant 22-32801885-G-A is Benign according to our data. Variant chr22-32801885-G-A is described in ClinVar as Benign. ClinVar VariationId is 341340.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00722 (1097/151974) while in subpopulation AFR AF = 0.023 (953/41504). AF 95% confidence interval is 0.0218. There are 10 homozygotes in GnomAd4. There are 526 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 1097 AD gene.

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	Effect	Exon Rank	Protein	UniProt
TIMP3	NM_000362.5	MANE Select	c.-117G>A	5_prime_UTR	Exon 1 of 5	NP_000353.1	P35625
SYN3	NM_003490.4	MANE Select	c.711+63030C>T	intron	N/A	NP_003481.3
SYN3	NM_001369907.1		c.711+63030C>T	intron	N/A	NP_001356836.1	O14994

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TIMP3	ENST00000266085.7	TSL:1 MANE Select	c.-117G>A	5_prime_UTR	Exon 1 of 5	ENSP00000266085.5	P35625
SYN3	ENST00000358763.7	TSL:5 MANE Select	c.711+63030C>T	intron	N/A	ENSP00000351614.2	O14994
TIMP3	ENST00000908983.1		c.-117G>A	5_prime_UTR	Exon 1 of 6	ENSP00000579042.1

Frequencies

GnomAD3 genomes

AF:

0.00718

AC:

1091

AN:

151866

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0229

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00446

Gnomad ASJ

AF:

0.00433

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00318

Gnomad NFE

AF:

0.000545

Gnomad OTH

AF:

0.0105

GnomAD4 exome

AF:

0.00103

AC:

1214

AN:

1174712

Hom.:

Cov.:

AF XY:

0.000965

AC XY:

553

AN XY:

573062

show subpopulations

African (AFR)

AF:

0.0220

AC:

497

AN:

22544

American (AMR)

AF:

0.00385

AC:

AN:

10134

Ashkenazi Jewish (ASJ)

AF:

0.00387

AC:

AN:

15264

East Asian (EAS)

AF:

0.00

AC:

AN:

24980

South Asian (SAS)

AF:

0.0000391

AC:

AN:

51164

European-Finnish (FIN)

AF:

0.00

AC:

AN:

27968

Middle Eastern (MID)

AF:

0.00398

AC:

AN:

3264

European-Non Finnish (NFE)

AF:

0.000490

AC:

476

AN:

971982

Other (OTH)

AF:

0.00270

AC:

128

AN:

47412

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

Heterozygous variant carriers

114

170

227

284

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

150

<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:

0.00722

AC:

1097

AN:

151974

Hom.:

Cov.:

AF XY:

0.00708

AC XY:

526

AN XY:

74300

show subpopulations

African (AFR)

AF:

0.0230

AC:

953

AN:

41504

American (AMR)

AF:

0.00445

AC:

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.00433

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5138

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10518

Middle Eastern (MID)

AF:

0.00685

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000545

AC:

AN:

67942

Other (OTH)

AF:

0.0104

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

113

170

226

283

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00698

Hom.:

Bravo

AF:

0.00858

Asia WGS

AF:

0.00174

AC:

AN:

3456

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Sorsby fundus dystrophy (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.46

CADD

Benign

(source)

DANN

Benign

0.97

PhyloP100

3.7

PromoterAI

0.038

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=297/3

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over