3-12158744-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_003256.4(TIMP4):c.97G>A(p.Ala33Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000609 in 1,608,884 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000066 (0 hom.)
• Consequence: TIMP4 NM_003256.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.77

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TIMP4	NM_003256.4	c.97G>A	p.Ala33Thr	missense_variant	1/5	ENST00000287814.5
SYN2	NM_133625.6	c.775-2802C>T		intron_variant		ENST00000621198.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TIMP4	ENST00000287814.5	c.97G>A	p.Ala33Thr	missense_variant	1/5	1	NM_003256.4	P1
SYN2	ENST00000621198.5	c.775-2802C>T		intron_variant		1	NM_133625.6	P2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152254 Hom.: 0 Cov.: 32

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000125 AC: 30 AN: 239932 Hom.: 0 AF XY: 0.000167 AC XY: 22 AN XY: 131514

Gnomad AFR exome AF: 0.0000669

Gnomad AMR exome AF: 0.0000582

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000230

Gnomad FIN exome AF: 0.000389

Gnomad NFE exome AF: 0.000120

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000659 AC: 96 AN: 1456630 Hom.: 0 Cov.: 31 AF XY: 0.0000745 AC XY: 54 AN XY: 724888

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: 0.000128

Gnomad4 FIN exome AF: 0.000328

Gnomad4 NFE exome AF: 0.0000567

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152254 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74382

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: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000453

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000117 AC: 1

ExAC AF: 0.000132 AC: 16

EpiCase AF: 0.000164

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

Aug 21, 2023

The c.97G>A (p.A33T) alteration is located in exon 1 (coding exon 1) of the TIMP4 gene. This alteration results from a G to A substitution at nucleotide position 97, causing the alanine (A) at amino acid position 33 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	Benign	0.15
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.090
Cadd	Uncertain	24
Dann	Pathogenic	1.0
DEOGEN2	Uncertain	0.60	D
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Benign	0.57	D
LIST_S2	Uncertain	0.94	D
M_CAP	Pathogenic	0.33	D
MetaRNN	Uncertain	0.51	D
MetaSVM	Uncertain	0.60	D
MutationAssessor	Uncertain	2.5	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.53
Sift	Benign	0.16	T
Sift4G	Uncertain	0.059	T
Polyphen		1.0	D
Vest4		0.30
MVP		0.89
MPC		0.37
ClinPred		0.21	T
GERP RS		4.6
Varity_R		0.13
gMVP		0.37

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: rs368008557; hg19: chr3-12200244;