22-32801885-G-A

Position:

• chr22-32801885-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BS1 BS2

The NM_000362.5(TIMP3):​c.-117G>A variant causes a 5 prime UTR change. The variant allele was found at a frequency of 0.00174 in 1,326,686 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0072 (10 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (11 hom.)
• Consequence: TIMP3 NM_000362.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.68

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 22-32801885-G-A is Benign according to our data. Variant chr22-32801885-G-A is described in ClinVar as [Benign]. Clinvar id is 341340.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00722 (1097/151974) while in subpopulation AFR AF= 0.023 (953/41504). AF 95% confidence interval is 0.0218. There are 10 homozygotes in gnomad4. There are 526 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1097 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TIMP3	NM_000362.5	c.-117G>A		5_prime_UTR_variant	1/5	ENST00000266085.7
SYN3	NM_003490.4	c.711+63030C>T		intron_variant		ENST00000358763.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TIMP3	ENST00000266085.7	c.-117G>A		5_prime_UTR_variant	1/5	1	NM_000362.5	P1
SYN3	ENST00000358763.7	c.711+63030C>T		intron_variant		5	NM_003490.4	P1
SYN3	ENST00000462268.1	n.225+63030C>T		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00718 AC: 1091 AN: 151866 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.0229

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00446

Gnomad ASJ AF: 0.00433

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000545

Gnomad OTH AF: 0.0105

GnomAD4 exome AF: 0.00103 AC: 1214 AN: 1174712 Hom.: 11 Cov.: 20 AF XY: 0.000965 AC XY: 553 AN XY: 573062

Gnomad4 AFR exome AF: 0.0220

Gnomad4 AMR exome AF: 0.00385

Gnomad4 ASJ exome AF: 0.00387

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000391

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000490

Gnomad4 OTH exome AF: 0.00270

GnomAD4 genome AF: 0.00722 AC: 1097 AN: 151974 Hom.: 10 Cov.: 32 AF XY: 0.00708 AC XY: 526 AN XY: 74300

Gnomad4 AFR AF: 0.0230

Gnomad4 AMR AF: 0.00445

Gnomad4 ASJ AF: 0.00433

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000545

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.00576 Hom.: 1

Bravo AF: 0.00858

Asia WGS AF: 0.00174 AC: 6 AN: 3456

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Sorsby fundus dystrophy Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	21
DANN	Benign	0.97
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs191293675; hg19: chr22-33197871;