22-32857293-T-C

Variant names:

• chr22-32857293-T-C
• rs9862
• NM_000362.5:c.249T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 4.55
• Publications: 60 publications found

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

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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TIMP3	NM_000362.5	c.249T>C	p.His83His	synonymous_variant	Exon 3 of 5	ENST00000266085.7	NP_000353.1
SYN3	NM_003490.4	c.711+7622A>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.249T>C	p.His83His	synonymous_variant	Exon 3 of 5	1	NM_000362.5	ENSP00000266085.5
SYN3	ENST00000358763.7	c.711+7622A>G		intron_variant	Intron 6 of 13	5	NM_003490.4	ENSP00000351614.2
SYN3	ENST00000462268.1	n.225+7622A>G		intron_variant	Intron 2 of 2	3

Frequencies

GnomAD3 genomes AF: 0.609 AC: 92549 AN: 151848 Hom.: 29934 Cov.: 31

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

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.: 49 AF XY: 0.514 AC XY: 373521 AN XY: 726704

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

GnomAD4 genome AF: 0.610 AC: 92670 AN: 151966 Hom.: 29994 Cov.: 31 AF XY: 0.607 AC XY: 45041 AN XY: 74258

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

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

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sorsby fundus dystrophy Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Sep 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Fundus dystrophy, pseudoinflammatory, recessive form Benign:1

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	12
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)

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

Other links and lift over

dbSNP: rs9862; hg19: chr22-33253280; COSMIC: COSV56662105;