rs17035945

Variant names:

• chr3-12153128-C-T
• rs17035945
• NM_003256.4:c.*387G>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 11 publications found

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

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
TIMP4	NM_003256.4	c.*387G>A		3_prime_UTR_variant	Exon 5 of 5	ENST00000287814.5	NP_003247.1
SYN2	NM_133625.6	c.774+1802C>T		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.*387G>A		3_prime_UTR_variant	Exon 5 of 5	1	NM_003256.4	ENSP00000287814.4
SYN2	ENST00000621198.5	c.774+1802C>T		intron_variant	Intron 5 of 12	1	NM_133625.6	ENSP00000480050.1
SYN2	ENST00000620175.4	c.774+1802C>T		intron_variant	Intron 5 of 10	1		ENSP00000484916.1
SYN2	ENST00000439861.5	n.225+1802C>T		intron_variant	Intron 2 of 9	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

African (AFR) AF: 0.314 AC: 1662 AN: 5288

American (AMR) AF: 0.0919 AC: 773 AN: 8410

Ashkenazi Jewish (ASJ) AF: 0.156 AC: 571 AN: 3652

East Asian (EAS) AF: 0.113 AC: 966 AN: 8526

South Asian (SAS) AF: 0.106 AC: 1871 AN: 17660

European-Finnish (FIN) AF: 0.114 AC: 665 AN: 5840

Middle Eastern (MID) AF: 0.112 AC: 62 AN: 552

European-Non Finnish (NFE) AF: 0.111 AC: 8526 AN: 77016

Other (OTH) AF: 0.125 AC: 926 AN: 7380

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

African (AFR) AF: 0.316 AC: 13112 AN: 41488

American (AMR) AF: 0.131 AC: 1996 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.177 AC: 615 AN: 3466

East Asian (EAS) AF: 0.124 AC: 644 AN: 5182

South Asian (SAS) AF: 0.129 AC: 619 AN: 4810

European-Finnish (FIN) AF: 0.120 AC: 1270 AN: 10598

Middle Eastern (MID) AF: 0.150 AC: 44 AN: 294

European-Non Finnish (NFE) AF: 0.119 AC: 8128 AN: 68020

Other (OTH) AF: 0.139 AC: 293 AN: 2114

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
PhyloP100		-0.79
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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