chr3-12157117-A-C

Position:

• chr3-12157117-A-C

Variant summary

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

The NM_133625.6(SYN2):​c.775-4429A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0803 in 152,196 control chromosomes in the GnomAD database, including 866 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 0.080 (866 hom., cov: 32)
• Consequence: SYN2 NM_133625.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.249

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=-0.88).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.181 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TIMP4	NM_003256.4	c.238-183T>G		intron_variant		ENST00000287814.5
SYN2	NM_133625.6	c.775-4429A>C		intron_variant		ENST00000621198.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TIMP4	ENST00000287814.5	c.238-183T>G		intron_variant		1	NM_003256.4	P1
SYN2	ENST00000621198.5	c.775-4429A>C		intron_variant		1	NM_133625.6	P2
SYN2	ENST00000620175.4	c.775-4429A>C		intron_variant		1		A2
SYN2	ENST00000439861.5	n.226-4429A>C		intron_variant, non_coding_transcript_variant		2

Frequencies

GnomAD3 genomes AF: 0.0804 AC: 12224 AN: 152078 Hom.: 865 Cov.: 32

Gnomad AFR AF: 0.180

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.0410

Gnomad ASJ AF: 0.0343

Gnomad EAS AF: 0.191

Gnomad SAS AF: 0.0442

Gnomad FIN AF: 0.0254

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.0348

Gnomad OTH AF: 0.0745

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0803 AC: 12227 AN: 152196 Hom.: 866 Cov.: 32 AF XY: 0.0785 AC XY: 5846 AN XY: 74426

Gnomad4 AFR AF: 0.180

Gnomad4 AMR AF: 0.0409

Gnomad4 ASJ AF: 0.0343

Gnomad4 EAS AF: 0.191

Gnomad4 SAS AF: 0.0437

Gnomad4 FIN AF: 0.0254

Gnomad4 NFE AF: 0.0347

Gnomad4 OTH AF: 0.0737

Alfa AF: 0.0164 Hom.: 12

Bravo AF: 0.0881

Asia WGS AF: 0.0910 AC: 315 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.76
DANN	Benign	0.46

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: rs2279750; hg19: chr3-12198617;