chr3-12153699-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_003256.4(TIMP4):ā€‹c.491A>Gā€‹(p.Tyr164Cys) variant causes a missense change. The variant allele was found at a frequency of 0.00000929 in 1,614,072 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: š‘“ 0.0000066 ( 0 hom., cov: 32)
Exomes š‘“: 0.0000096 ( 0 hom. )

Consequence

TIMP4
NM_003256.4 missense

Scores

8
8
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.89
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 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.862

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
TIMP4NM_003256.4 linkuse as main transcriptc.491A>G p.Tyr164Cys missense_variant 5/5 ENST00000287814.5
SYN2NM_133625.6 linkuse as main transcriptc.774+2373T>C intron_variant ENST00000621198.5

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TIMP4ENST00000287814.5 linkuse as main transcriptc.491A>G p.Tyr164Cys missense_variant 5/51 NM_003256.4 P1
SYN2ENST00000621198.5 linkuse as main transcriptc.774+2373T>C intron_variant 1 NM_133625.6 P2Q92777-1
SYN2ENST00000620175.4 linkuse as main transcriptc.774+2373T>C intron_variant 1 A2Q92777-2
SYN2ENST00000439861.5 linkuse as main transcriptn.225+2373T>C intron_variant, non_coding_transcript_variant 2

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152178
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000119
AC:
3
AN:
251416
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135866
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000958
AC:
14
AN:
1461894
Hom.:
0
Cov.:
31
AF XY:
0.00000825
AC XY:
6
AN XY:
727248
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000989
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152178
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74364
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000655
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000151
ExAC
AF:
0.00000824
AC:
1

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 GeneticsMar 07, 2024The c.491A>G (p.Y164C) alteration is located in exon 5 (coding exon 5) of the TIMP4 gene. This alteration results from a A to G substitution at nucleotide position 491, causing the tyrosine (Y) at amino acid position 164 to be replaced by a cysteine (C). 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
0.64
BayesDel_addAF
Pathogenic
0.22
D
BayesDel_noAF
Pathogenic
0.16
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.69
D
Eigen
Uncertain
0.66
Eigen_PC
Uncertain
0.62
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.91
D
M_CAP
Pathogenic
0.37
D
MetaRNN
Pathogenic
0.86
D
MetaSVM
Pathogenic
0.85
D
MutationAssessor
Uncertain
2.4
M
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.67
T
PROVEAN
Uncertain
-2.5
D
REVEL
Pathogenic
0.76
Sift
Benign
0.18
T
Sift4G
Benign
0.18
T
Polyphen
1.0
D
Vest4
0.74
MutPred
0.48
Loss of glycosylation at T162 (P = 0.0602);
MVP
0.89
MPC
0.43
ClinPred
0.91
D
GERP RS
4.9
Varity_R
0.16
gMVP
0.68

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
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: rs113458928; hg19: chr3-12195199; API