22-32802053-G-C

Variant names:

• chr22-32802053-G-C
• rs1324470172
• NM_000362.5:c.52G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000362.5(TIMP3):​c.52G>C​(p.Asp18His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000702 in 1,424,800 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D18G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: TIMP3 NM_000362.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.224
• Publications: 1 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09399143).

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.52G>C	p.Asp18His	missense	Exon 1 of 5	NP_000353.1	P35625
	SYN3	NM_003490.4	MANE Select	c.711+62862C>G		intron	N/A	NP_003481.3
	SYN3	NM_001369907.1		c.711+62862C>G		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.52G>C	p.Asp18His	missense	Exon 1 of 5	ENSP00000266085.5	P35625
	SYN3	ENST00000358763.7	TSL:5 MANE Select	c.711+62862C>G		intron	N/A	ENSP00000351614.2	O14994
	TIMP3	ENST00000908983.1		c.52G>C	p.Asp18His	missense	Exon 1 of 6	ENSP00000579042.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000555 AC: 1 AN: 180142 AF XY: 0.0000101

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000129

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.02e-7 AC: 1 AN: 1424800 Hom.: 0 Cov.: 31 AF XY: 0.00000142 AC XY: 1 AN XY: 706220

African (AFR) AF: 0.00 AC: 0 AN: 33018

American (AMR) AF: 0.00 AC: 0 AN: 40178

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 38110

South Asian (SAS) AF: 0.00 AC: 0 AN: 81804

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42930

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5734

European-Non Finnish (NFE) AF: 9.11e-7 AC: 1 AN: 1098286

Other (OTH) AF: 0.00 AC: 0 AN: 59250

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.060	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	10
DANN	Benign	0.93
DEOGEN2	Benign	0.23	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.44	T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.094	T
MetaSVM	Benign	-0.46	T
MutationAssessor	Benign	0.95	L
PhyloP100		-0.22
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.69	N
REVEL	Benign	0.28
Sift	Benign	0.26	T
Sift4G	Benign	0.075	T
Polyphen		0.0	B
Vest4		0.087
MutPred		0.26		Gain of loop (P = 0.0851)
MVP		0.89
MPC		1.2
ClinPred		0.070	T
GERP RS		-4.8
PromoterAI		-0.027	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.089
gMVP		0.33
Mutation Taster		=91/9	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: rs1324470172; hg19: chr22-33198039;