chr3-12154421-A-G

Variant names:

• chr3-12154421-A-G
• NM_003256.4:c.383T>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_003256.4(TIMP4):​c.383T>C​(p.Ile128Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TIMP4 NM_003256.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.05

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.765

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TIMP4	NM_003256.4	c.383T>C	p.Ile128Thr	missense_variant	Exon 4 of 5	ENST00000287814.5	NP_003247.1
SYN2	NM_133625.6	c.774+3095A>G		intron_variant	Intron 5 of 12	ENST00000621198.5	NP_598328.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TIMP4	ENST00000287814.5	c.383T>C	p.Ile128Thr	missense_variant	Exon 4 of 5	1	NM_003256.4	ENSP00000287814.4
SYN2	ENST00000621198.5	c.774+3095A>G		intron_variant	Intron 5 of 12	1	NM_133625.6	ENSP00000480050.1
SYN2	ENST00000620175.4	c.774+3095A>G		intron_variant	Intron 5 of 10	1		ENSP00000484916.1
SYN2	ENST00000439861.5	n.225+3095A>G		intron_variant	Intron 2 of 9	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461872 Hom.: 0 Cov.: 31 AF XY: 0.00000275 AC XY: 2 AN XY: 727232

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.66	D
Eigen	Benign	0.11
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.77	D
MetaSVM	Uncertain	0.36	D
MutationAssessor	Benign	1.4	L
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.62
Sift	Benign	0.38	T
Sift4G	Benign	0.36	T
Polyphen		0.19	B
Vest4		0.59
MutPred		0.70		Loss of stability (P = 0.0067);
MVP		0.71
MPC		0.40
ClinPred		0.92	D
GERP RS		4.9
Varity_R		0.11
gMVP		0.81

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-12195921;