chr22-32857293-T-C

Position:

chr22-32857293-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000362.5(TIMP3):c.249T>C(p.His83=) 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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 4.55

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 made for transcript

Verdict is Benign. Variant got -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. Variant chr22-32857293-T-C is described in Lovd as [Benign]. Variant chr22-32857293-T-C is described in Lovd as [Likely_benign].

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/exons	MANE	Protein	UniProt
TIMP3	NM_000362.5 linkuse as main transcript	c.249T>C	p.His83=	synonymous_variant	3/5	ENST00000266085.7	NP_000353.1
SYN3	NM_003490.4 linkuse as main transcript	c.711+7622A>G		intron_variant		ENST00000358763.7	NP_003481.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
TIMP3	ENST00000266085.7 linkuse as main transcript	c.249T>C	p.His83=	synonymous_variant	3/5	1	NM_000362.5	ENSP00000266085	P1
SYN3	ENST00000358763.7 linkuse as main transcript	c.711+7622A>G		intron_variant		5	NM_003490.4	ENSP00000351614	P1
SYN3	ENST00000462268.1 linkuse as main transcript	n.225+7622A>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.609

AC:

92549

AN:

151848

Hom.:

29934

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.553

AC:

139046

AN:

251376

Hom.:

40026

AF XY:

0.541

AC XY:

73516

AN XY:

135852

show subpopulations

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 SAS exome

AF:

0.537

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.:

AF XY:

0.514

AC XY:

373521

AN XY:

726704

show subpopulations

Gnomad4 AFR exome

AF:

0.845

Gnomad4 AMR exome

AF:

0.703

Gnomad4 ASJ exome

AF:

0.549

Gnomad4 EAS exome

AF:

0.643

Gnomad4 SAS exome

AF:

0.535

Gnomad4 FIN exome

AF:

0.429

Gnomad4 NFE exome

AF:

0.494

Gnomad4 OTH exome

AF:

0.538

GnomAD4 genome

AF:

0.610

AC:

92670

AN:

151966

Hom.:

29994

Cov.:

AF XY:

0.607

AC XY:

45041

AN XY:

74258

show subpopulations

Gnomad4 AFR

AF:

0.835

Gnomad4 AMR

AF:

0.665

Gnomad4 ASJ

AF:

0.536

Gnomad4 EAS

AF:

0.609

Gnomad4 SAS

AF:

0.534

Gnomad4 FIN

AF:

0.438

Gnomad4 NFE

AF:

0.495

Gnomad4 OTH

AF:

0.591

Alfa

AF:

0.525

Hom.:

35200

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

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Sorsby fundus dystrophy

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

- -

Fundus dystrophy, pseudoinflammatory, recessive form

Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.60

CADD

Benign

DANN

Benign

0.89

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over