chr22-32801885-G-A

Variant names:

• chr22-32801885-G-A
• rs191293675
• NM_000362.5:c.-117G>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong 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, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.68
• Publications: 2 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 -18 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_multiple_submitters_no_conflicts, 2 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1097 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TIMP3	NM_000362.5	c.-117G>A		5_prime_UTR_variant	Exon 1 of 5	ENST00000266085.7	NP_000353.1
SYN3	NM_003490.4	c.711+63030C>T		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.-117G>A		5_prime_UTR_variant	Exon 1 of 5	1	NM_000362.5	ENSP00000266085.5
SYN3	ENST00000358763.7	c.711+63030C>T		intron_variant	Intron 6 of 13	5	NM_003490.4	ENSP00000351614.2
SYN3	ENST00000462268.1	n.225+63030C>T		intron_variant	Intron 2 of 2	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

African (AFR) AF: 0.0220 AC: 497 AN: 22544

American (AMR) AF: 0.00385 AC: 39 AN: 10134

Ashkenazi Jewish (ASJ) AF: 0.00387 AC: 59 AN: 15264

East Asian (EAS) AF: 0.00 AC: 0 AN: 24980

South Asian (SAS) AF: 0.0000391 AC: 2 AN: 51164

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 27968

Middle Eastern (MID) AF: 0.00398 AC: 13 AN: 3264

European-Non Finnish (NFE) AF: 0.000490 AC: 476 AN: 971982

Other (OTH) AF: 0.00270 AC: 128 AN: 47412

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

African (AFR) AF: 0.0230 AC: 953 AN: 41504

American (AMR) AF: 0.00445 AC: 68 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00433 AC: 15 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5138

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10518

Middle Eastern (MID) AF: 0.00685 AC: 2 AN: 292

European-Non Finnish (NFE) AF: 0.000545 AC: 37 AN: 67942

Other (OTH) AF: 0.0104 AC: 22 AN: 2108

Alfa AF: 0.00698 Hom.: 1

Bravo AF: 0.00858

Asia WGS AF: 0.00174 AC: 6 AN: 3456

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Sorsby fundus dystrophy Benign:1

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. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	21
DANN	Benign	0.97
PhyloP100		3.7
PromoterAI		0.038	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=297/3	polymorphism

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: rs191293675; hg19: chr22-33197871;