chr22-32802048-T-C

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_000362.5(TIMP3):c.47T>C(p.Leu16Pro) variant causes a missense change. The variant allele was found at a frequency of 0.0000014 in 1,423,722 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

TIMP3
NM_000362.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.79

Publications

0 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.885

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TIMP3	NM_000362.5 link	c.47T>C	p.Leu16Pro	missense_variant	Exon 1 of 5	ENST00000266085.7	NP_000353.1	P35625
SYN3	NM_003490.4 link	c.711+62867A>G		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.47T>C	p.Leu16Pro	missense_variant	Exon 1 of 5	1	NM_000362.5	ENSP00000266085.5	P35625
SYN3	ENST00000358763.7 link	c.711+62867A>G		intron_variant	Intron 6 of 13	5	NM_003490.4	ENSP00000351614.2	O14994
SYN3	ENST00000462268.1 link	n.225+62867A>G		intron_variant	Intron 2 of 2	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

178030

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000140

AC:

AN:

1423722

Hom.:

Cov.:

AF XY:

0.00000142

AC XY:

AN XY:

705542

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33006

American (AMR)

AF:

0.00

AC:

AN:

40018

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25456

East Asian (EAS)

AF:

0.00

AC:

AN:

38056

South Asian (SAS)

AF:

0.00

AC:

AN:

81704

European-Finnish (FIN)

AF:

0.00

AC:

AN:

42856

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5730

European-Non Finnish (NFE)

AF:

9.11e-7

AC:

AN:

1097678

Other (OTH)

AF:

0.0000169

AC:

AN:

59218

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

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 22, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.47T>C (p.L16P) alteration is located in exon 1 (coding exon 1) of the TIMP3 gene. This alteration results from a T to C substitution at nucleotide position 47, causing the leucine (L) at amino acid position 16 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Pathogenic

0.39

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.32

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.67

M_CAP

Pathogenic

0.66

MetaRNN

Pathogenic

0.89

MetaSVM

Pathogenic

0.90

MutationAssessor

Benign

1.5

PhyloP100

4.8

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-1.2

REVEL

Pathogenic

0.76

Sift

Uncertain

0.0070

Sift4G

Benign

0.13

Polyphen

0.99

Vest4

0.89

MutPred

0.63

Gain of loop (P = 0.0013);

MVP

1.0

MPC

2.1

ClinPred

0.89

GERP RS

5.0

PromoterAI

-0.014

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.73

gMVP

0.71

Mutation Taster

=47/53

disease causing

(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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over