chr22-32802008-C-A

Variant names:

• chr22-32802008-C-A
• rs777890618
• NM_000362.5:c.7C>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_000362.5(TIMP3):​c.7C>A​(p.Pro3Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000419 in 1,431,514 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts 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. P3S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000042 (0 hom.)
• Consequence: TIMP3 NM_000362.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.82
• 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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.25796872).
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TIMP3	NM_000362.5	c.7C>A	p.Pro3Thr	missense_variant	Exon 1 of 5	ENST00000266085.7	NP_000353.1
SYN3	NM_003490.4	c.711+62907G>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.7C>A	p.Pro3Thr	missense_variant	Exon 1 of 5	1	NM_000362.5	ENSP00000266085.5
SYN3	ENST00000358763.7	c.711+62907G>T		intron_variant	Intron 6 of 13	5	NM_003490.4	ENSP00000351614.2
SYN3	ENST00000462268.1	n.225+62907G>T		intron_variant	Intron 2 of 2	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000209 AC: 4 AN: 191024 AF XY: 0.0000189

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: 0.0000480

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000419 AC: 6 AN: 1431514 Hom.: 0 Cov.: 30 AF XY: 0.00000422 AC XY: 3 AN XY: 710304

African (AFR) AF: 0.00 AC: 0 AN: 33150

American (AMR) AF: 0.00 AC: 0 AN: 41598

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25650

East Asian (EAS) AF: 0.00 AC: 0 AN: 38558

South Asian (SAS) AF: 0.0000121 AC: 1 AN: 82680

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42164

Middle Eastern (MID) AF: 0.000179 AC: 1 AN: 5596

European-Non Finnish (NFE) AF: 0.00000272 AC: 3 AN: 1102656

Other (OTH) AF: 0.0000168 AC: 1 AN: 59462

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000172 AC: 2

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.096
Eigen_PC	Benign	0.061
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.72	T
M_CAP	Pathogenic	0.48	D
MetaRNN	Benign	0.26	T
MetaSVM	Uncertain	-0.065	T
MutationAssessor	Benign	1.1	L
PhyloP100		1.8
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	0.43	N
REVEL	Uncertain	0.33
Sift	Uncertain	0.0080	D
Sift4G	Benign	0.089	T
Polyphen		0.15	B
Vest4		0.21
MutPred		0.42		Loss of loop (P = 0.0288);
MVP		0.97
MPC		1.2
ClinPred		0.16	T
GERP RS		5.0
PromoterAI		0.021	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.15
gMVP		0.66
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: rs777890618; hg19: chr22-33197994;