rs17035945

Positions:

• chr3-12153128-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003256.4(TIMP4):​c.*387G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.149 in 286,494 control chromosomes in the GnomAD database, including 4,054 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.18 (2921 hom., cov: 32)
  • Exomes 𝑓: 0.12 (1133 hom.)
• Consequence: TIMP4 NM_003256.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.792

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.312 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TIMP4	NM_003256.4	c.*387G>A		3_prime_UTR_variant	5/5	ENST00000287814.5	NP_003247.1
SYN2	NM_133625.6	c.774+1802C>T		intron_variant		ENST00000621198.5	NP_598328.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TIMP4	ENST00000287814.5	c.*387G>A		3_prime_UTR_variant	5/5	1	NM_003256.4	ENSP00000287814	P1
SYN2	ENST00000621198.5	c.774+1802C>T		intron_variant		1	NM_133625.6	ENSP00000480050	P2
SYN2	ENST00000620175.4	c.774+1802C>T		intron_variant		1		ENSP00000484916	A2
SYN2	ENST00000439861.5	n.225+1802C>T		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.175 AC: 26677 AN: 152052 Hom.: 2912 Cov.: 32

Gnomad AFR AF: 0.316

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.131

Gnomad ASJ AF: 0.177

Gnomad EAS AF: 0.124

Gnomad SAS AF: 0.128

Gnomad FIN AF: 0.120

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.119

Gnomad OTH AF: 0.139

GnomAD4 exome AF: 0.119 AC: 16022 AN: 134324 Hom.: 1133 Cov.: 0 AF XY: 0.117 AC XY: 8161 AN XY: 69498

Gnomad4 AFR exome AF: 0.314

Gnomad4 AMR exome AF: 0.0919

Gnomad4 ASJ exome AF: 0.156

Gnomad4 EAS exome AF: 0.113

Gnomad4 SAS exome AF: 0.106

Gnomad4 FIN exome AF: 0.114

Gnomad4 NFE exome AF: 0.111

Gnomad4 OTH exome AF: 0.125

GnomAD4 genome AF: 0.176 AC: 26727 AN: 152170 Hom.: 2921 Cov.: 32 AF XY: 0.175 AC XY: 13030 AN XY: 74400

Gnomad4 AFR AF: 0.316

Gnomad4 AMR AF: 0.131

Gnomad4 ASJ AF: 0.177

Gnomad4 EAS AF: 0.124

Gnomad4 SAS AF: 0.129

Gnomad4 FIN AF: 0.120

Gnomad4 NFE AF: 0.119

Gnomad4 OTH AF: 0.139

Alfa AF: 0.141 Hom.: 359

Bravo AF: 0.182

Asia WGS AF: 0.167 AC: 579 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.28
DANN	Benign	0.51

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: rs17035945; hg19: chr3-12194628; COSMIC: COSV55139933; COSMIC: COSV55139933;