rs137853299

Positions:

• chr22-32859313-A-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_000362.5(TIMP3):​c.572A>G​(p.Tyr191Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TIMP3 NM_000362.5 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 5.88

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 Pathogenic. Variant got 10 ACMG points.

• PM1: In a disulfide_bond (size 47) in uniprot entity TIMP3_HUMAN there are 13 pathogenic changes around while only 0 benign (100%) in NM_000362.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.969
• PP5: Variant 22-32859313-A-G is Pathogenic according to our data. Variant chr22-32859313-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 12677.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr22-32859313-A-G is described in Lovd as [Pathogenic]. Variant chr22-32859313-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TIMP3	NM_000362.5	c.572A>G	p.Tyr191Cys	missense_variant	5/5	ENST00000266085.7	NP_000353.1
SYN3	NM_003490.4	c.711+5602T>C		intron_variant		ENST00000358763.7	NP_003481.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TIMP3	ENST00000266085.7	c.572A>G	p.Tyr191Cys	missense_variant	5/5	1	NM_000362.5	ENSP00000266085.5
SYN3	ENST00000358763.7	c.711+5602T>C		intron_variant		5	NM_003490.4	ENSP00000351614.2
SYN3	ENST00000462268.1	n.225+5602T>C		intron_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Sorsby fundus dystrophy Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 1994

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 03, 2023

This sequence change replaces tyrosine, which is neutral and polar, with cysteine, which is neutral and slightly polar, at codon 191 of the TIMP3 protein (p.Tyr191Cys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Sorsby fundus dystrophy (PMID: 7894485, 27601084). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12677). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.69	D
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Uncertain	2.1	M
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-1.1	N
REVEL	Pathogenic	0.85
Sift	Benign	0.039	D
Sift4G	Benign	0.093	T
Polyphen		1.0	D
Vest4		0.89
MutPred		0.86		Gain of methylation at K188 (P = 0.047);
MVP		1.0
MPC		2.3
ClinPred		0.93	D
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.54
gMVP		0.87

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: rs137853299; hg19: chr22-33255300;