22-32802035-G-C

Variant names:

• chr22-32802035-G-C
• rs2046600889
• NM_000362.5:c.34G>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The NM_000362.5(TIMP3):​c.34G>C​(p.Gly12Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TIMP3 NM_000362.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 2.14

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]

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 22-32802035-G-C is Pathogenic according to our data. Variant chr22-32802035-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 866542.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TIMP3	NM_000362.5	c.34G>C	p.Gly12Arg	missense_variant	Exon 1 of 5	ENST00000266085.7	NP_000353.1
SYN3	NM_003490.4	c.711+62880C>G		intron_variant	Intron 6 of 13	ENST00000358763.7	NP_003481.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TIMP3	ENST00000266085.7	c.34G>C	p.Gly12Arg	missense_variant	Exon 1 of 5	1	NM_000362.5	ENSP00000266085.5
SYN3	ENST00000358763.7	c.711+62880C>G		intron_variant	Intron 6 of 13	5	NM_003490.4	ENSP00000351614.2
SYN3	ENST00000462268.1	n.225+62880C>G		intron_variant	Intron 2 of 2	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1

Nov 06, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 12 of the TIMP3 protein (p.Gly12Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with retinopathy (PMID: 35679059). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 866542). 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 tolerated. Experimental studies have shown that this missense change affects TIMP3 function (PMID: 35679059). For these reasons, this variant has been classified as Pathogenic. -

Retinal dystrophy Uncertain:1

Jan 29, 2019

Blueprint Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	T
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.81	T
M_CAP	Uncertain	0.24	D
MetaRNN	Uncertain	0.69	D
MetaSVM	Benign	-0.34	T
MutationAssessor	Benign	1.6	L
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.41	N
REVEL	Uncertain	0.56
Sift	Benign	0.36	T
Sift4G	Benign	0.35	T
Polyphen		0.15	B
Vest4		0.58
MutPred		0.78		Gain of MoRF binding (P = 0.1168);
MVP		0.91
MPC		1.4
ClinPred		0.17	T
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.064
gMVP		0.80

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

Other links and lift over

dbSNP: rs2046600889; hg19: chr22-33198021;