3-12158788-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_003256.4(TIMP4):c.53T>C(p.Leu18Pro) variant causes a missense change. The variant allele was found at a frequency of 0.0000193 in 1,450,530 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L18V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: TIMP4 NM_003256.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.56

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.939

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TIMP4	NM_003256.4	c.53T>C	p.Leu18Pro	missense_variant	1/5	ENST00000287814.5
SYN2	NM_133625.6	c.775-2758A>G		intron_variant		ENST00000621198.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TIMP4	ENST00000287814.5	c.53T>C	p.Leu18Pro	missense_variant	1/5	1	NM_003256.4	P1
SYN2	ENST00000621198.5	c.775-2758A>G		intron_variant		1	NM_133625.6	P2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000860 AC: 2 AN: 232472 Hom.: 0 AF XY: 0.00000780 AC XY: 1 AN XY: 128224

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 SAS exome AF: 0.0000330

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000947

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000193 AC: 28 AN: 1450530 Hom.: 0 Cov.: 31 AF XY: 0.0000166 AC XY: 12 AN XY: 721626

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: 0.0000232

Gnomad4 FIN exome AF: 0.0000221

Gnomad4 NFE exome AF: 0.0000216

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 12, 2021

The c.53T>C (p.L18P) 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 53, causing the leucine (L) at amino acid position 18 to be replaced by a proline (P). 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	Benign	0.12
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Pathogenic	0.21
Cadd	Pathogenic	27
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.57	D
Eigen	Benign	-0.073
Eigen_PC	Benign	0.046
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.55	T
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Uncertain	0.30	D
MutationAssessor	Pathogenic	3.0	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-3.5	D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0070	D
Polyphen		0.10	B
Vest4		0.89
MutPred		0.75		Gain of disorder (P = 0.0076);
MVP		0.79
MPC		0.48
ClinPred		0.98	D
GERP RS		3.6
Varity_R		0.79
gMVP		0.74

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

LitVar

Other links and lift over

dbSNP: rs924935644; hg19: chr3-12200288;