22-32802046-C-T

Variant names:

• chr22-32802046-C-T
• rs2145931146
• NM_000362.5:c.45C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Moderate BP6_Moderate BP7

The NM_000362.5(TIMP3):​c.45C>T​(p.Ser15Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TIMP3 NM_000362.5 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.751
• Publications: 0 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.33).
• BP6: Variant 22-32802046-C-T is Benign according to our data. Variant chr22-32802046-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1091978.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.751 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000362.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TIMP3	NM_000362.5	MANE Select	c.45C>T	p.Ser15Ser	synonymous	Exon 1 of 5	NP_000353.1	P35625
	SYN3	NM_003490.4	MANE Select	c.711+62869G>A		intron	N/A	NP_003481.3
	SYN3	NM_001369907.1		c.711+62869G>A		intron	N/A	NP_001356836.1	O14994

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TIMP3	ENST00000266085.7	TSL:1 MANE Select	c.45C>T	p.Ser15Ser	synonymous	Exon 1 of 5	ENSP00000266085.5	P35625
	SYN3	ENST00000358763.7	TSL:5 MANE Select	c.711+62869G>A		intron	N/A	ENSP00000351614.2	O14994
	TIMP3	ENST00000908983.1		c.45C>T	p.Ser15Ser	synonymous	Exon 1 of 6	ENSP00000579042.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1424466 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 705926

African (AFR) AF: 0.00 AC: 0 AN: 33016

American (AMR) AF: 0.00 AC: 0 AN: 40134

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25490

East Asian (EAS) AF: 0.00 AC: 0 AN: 38104

South Asian (SAS) AF: 0.00 AC: 0 AN: 81768

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42946

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5724

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1098044

Other (OTH) AF: 0.00 AC: 0 AN: 59240

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.33
CADD	Benign	14
DANN	Benign	0.96
PhyloP100		0.75
PromoterAI		-0.025	Neutral
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

Other links and lift over

dbSNP: rs2145931146; hg19: chr22-33198032;