3-12158719-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_003256.4(TIMP4):ā€‹c.122T>Cā€‹(p.Ile41Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000214 in 1,610,184 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.00012 ( 0 hom., cov: 33)
Exomes š‘“: 0.00022 ( 0 hom. )

Consequence

TIMP4
NM_003256.4 missense

Scores

2
5
12

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.46
Variant links:
Genes affected
TIMP4 (HGNC:11823): (TIMP metallopeptidase inhibitor 4) 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. The secreted, netrin domain-containing protein encoded by this gene is involved in regulation of platelet aggregation and recruitment and may play role in hormonal regulation and endometrial tissue remodeling. [provided by RefSeq, Jul 2008]
SYN2 (HGNC:11495): (synapsin II) 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. This member of the synapsin family encodes a neuron-specific phosphoprotein that selectively binds to small synaptic vesicles in the presynaptic nerve terminal. Polymorphisms in this gene are associated with abnormal presynaptic function and related neuronal disorders, including autism, epilepsy, bipolar disorder and schizophrenia. Alternative splicing of this gene results in multiple transcript variants. The tissue inhibitor of metalloproteinase 4 gene is located within an intron of this gene and is transcribed in the opposite direction. [provided by RefSeq, Feb 2014]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.39776528).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
TIMP4NM_003256.4 linkuse as main transcriptc.122T>C p.Ile41Thr missense_variant 1/5 ENST00000287814.5
SYN2NM_133625.6 linkuse as main transcriptc.775-2827A>G intron_variant ENST00000621198.5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TIMP4ENST00000287814.5 linkuse as main transcriptc.122T>C p.Ile41Thr missense_variant 1/51 NM_003256.4 P1
SYN2ENST00000621198.5 linkuse as main transcriptc.775-2827A>G intron_variant 1 NM_133625.6 P2Q92777-1

Frequencies

GnomAD3 genomes
AF:
0.000125
AC:
19
AN:
152232
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000250
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.0000826
AC:
20
AN:
242114
Hom.:
0
AF XY:
0.0000679
AC XY:
9
AN XY:
132504
show subpopulations
Gnomad AFR exome
AF:
0.0000662
Gnomad AMR exome
AF:
0.0000290
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000518
Gnomad NFE exome
AF:
0.000147
Gnomad OTH exome
AF:
0.000167
GnomAD4 exome
AF:
0.000223
AC:
325
AN:
1457952
Hom.:
0
Cov.:
31
AF XY:
0.000192
AC XY:
139
AN XY:
725514
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.0000448
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000800
Gnomad4 NFE exome
AF:
0.000273
Gnomad4 OTH exome
AF:
0.000249
GnomAD4 genome
AF:
0.000125
AC:
19
AN:
152232
Hom.:
0
Cov.:
33
AF XY:
0.0000672
AC XY:
5
AN XY:
74376
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000250
Gnomad4 OTH
AF:
0.000478
Alfa
AF:
0.000271
Hom.:
0
Bravo
AF:
0.000106
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.00
AC:
0
ExAC
AF:
0.0000497
AC:
6
EpiCase
AF:
0.000109
EpiControl
AF:
0.000178

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsFeb 13, 2023The c.122T>C (p.I41T) alteration is located in exon 1 (coding exon 1) of the TIMP4 gene. This alteration results from a T to C substitution at nucleotide position 122, causing the isoleucine (I) at amino acid position 41 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.57
BayesDel_addAF
Benign
-0.12
T
BayesDel_noAF
Benign
-0.15
CADD
Benign
23
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.67
D
Eigen
Benign
-0.31
Eigen_PC
Benign
-0.13
FATHMM_MKL
Benign
0.69
D
LIST_S2
Benign
0.61
T
M_CAP
Pathogenic
0.30
D
MetaRNN
Benign
0.40
T
MetaSVM
Benign
-0.29
T
MutationAssessor
Benign
0.69
N
MutationTaster
Benign
1.0
D;N
PrimateAI
Benign
0.48
T
PROVEAN
Benign
-1.8
N
REVEL
Uncertain
0.39
Sift
Uncertain
0.0010
D
Sift4G
Uncertain
0.0040
D
Polyphen
0.0050
B
Vest4
0.26
MVP
0.63
MPC
0.081
ClinPred
0.15
T
GERP RS
3.5
Varity_R
0.29
gMVP
0.55

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs199536325; hg19: chr3-12200219; API