3-12153588-A-G

Position:

• chr3-12153588-A-G

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_003256.4(TIMP4):​c.602T>C​(p.Val201Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000075 in 1,614,052 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000075 (0 hom.)
• Consequence: TIMP4 NM_003256.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.458

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_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.02554363).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TIMP4	NM_003256.4	c.602T>C	p.Val201Ala	missense_variant	5/5	ENST00000287814.5
SYN2	NM_133625.6	c.774+2262A>G		intron_variant		ENST00000621198.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TIMP4	ENST00000287814.5	c.602T>C	p.Val201Ala	missense_variant	5/5	1	NM_003256.4	P1
SYN2	ENST00000621198.5	c.774+2262A>G		intron_variant		1	NM_133625.6	P2
SYN2	ENST00000620175.4	c.774+2262A>G		intron_variant		1		A2
SYN2	ENST00000439861.5	n.225+2262A>G		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.0000788 AC: 12 AN: 152192 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

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: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000954 AC: 24 AN: 251480 Hom.: 0 AF XY: 0.000118 AC XY: 16 AN XY: 135910

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000132

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.0000746 AC: 109 AN: 1461860 Hom.: 0 Cov.: 30 AF XY: 0.0000701 AC XY: 51 AN XY: 727230

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000773

Gnomad4 OTH exome AF: 0.0000993

GnomAD4 genome AF: 0.0000788 AC: 12 AN: 152192 Hom.: 0 Cov.: 32 AF XY: 0.0000942 AC XY: 7 AN XY: 74348

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000823 Hom.: 0

Bravo AF: 0.0000604

ExAC AF: 0.0000988 AC: 12

EpiCase AF: 0.000164

EpiControl AF: 0.000178

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

Nov 09, 2023

The c.602T>C (p.V201A) alteration is located in exon 5 (coding exon 5) of the TIMP4 gene. This alteration results from a T to C substitution at nucleotide position 602, causing the valine (V) at amino acid position 201 to be replaced by an alanine (A). 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	0.058
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	0.35
DANN	Benign	0.82
DEOGEN2	Benign	0.35	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.040	N
LIST_S2	Benign	0.19	T
M_CAP	Uncertain	0.087	D
MetaRNN	Benign	0.026	T
MetaSVM	Benign	-0.49	T
MutationAssessor	Benign	-0.55	N
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	1.6	N
REVEL	Benign	0.23
Sift	Benign	0.52	T
Sift4G	Benign	0.60	T
Polyphen		0.0	B
Vest4		0.042
MutPred		0.43		Gain of relative solvent accessibility (P = 0.0098);
MVP		0.45
MPC		0.073
ClinPred		0.015	T
GERP RS		-8.3
Varity_R		0.025
gMVP		0.68

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

Other links and lift over

dbSNP: rs750207308; hg19: chr3-12195088;