rs6609533

chrX-47585887-A-GchrX-47585887-A-T

Variant summary

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

The ENST00000456754.6(TIMP1):c.*473A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.459 in 1,132,489 control chromosomes in the GnomAD database, including 81,322 homozygotes. There are 165,827 hemizygotes in GnomAD. 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 0.47 (8636 hom., 14936 hem., cov: 22)
  • Exomes 𝑓: 0.46 (72686 hom. 150891 hem.)
• Consequence: TIMP1 ENST00000456754.6 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.904

Genes affected

TIMP1 (HGNC:11820): (TIMP metallopeptidase inhibitor 1) This gene belongs to the TIMP gene family. The proteins encoded by this gene family are natural inhibitors of the matrix metalloproteinases (MMPs), a group of peptidases involved in degradation of the extracellular matrix. In addition to its inhibitory role against most of the known MMPs, the encoded protein is able to promote cell proliferation in a wide range of cell types, and may also have an anti-apoptotic function. Transcription of this gene is highly inducible in response to many cytokines and hormones. In addition, the expression from some but not all inactive X chromosomes suggests that this gene inactivation is polymorphic in human females. This gene is located within intron 6 of the synapsin I gene and is transcribed in the opposite direction. [provided by RefSeq, Jul 2008]

SYN1 (HGNC:11494): (synapsin I) 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 plays a role in regulation of axonogenesis and synaptogenesis. The protein encoded serves as a substrate for several different protein kinases and phosphorylation may function in the regulation of this protein in the nerve terminal. Mutations in this gene may be associated with X-linked disorders with primary neuronal degeneration such as Rett syndrome. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.49 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TIMP1	NM_003254.3	c.453+220A>G		intron_variant		ENST00000218388.9
SYN1	NM_006950.3	c.775-8386T>C		intron_variant		ENST00000295987.13
SYN1	NM_133499.2	c.775-8386T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TIMP1	ENST00000218388.9	c.453+220A>G		intron_variant		1	NM_003254.3	P1
SYN1	ENST00000295987.13	c.775-8386T>C		intron_variant		2	NM_006950.3	P3

Frequencies

GnomAD3 genomes AF: 0.467 AC: 51307 AN: 109809 Hom.: 8627 Cov.: 22 AF XY: 0.464 AC XY: 14896 AN XY: 32099

Gnomad AFR AF: 0.495

Gnomad AMI AF: 0.398

Gnomad AMR AF: 0.440

Gnomad ASJ AF: 0.437

Gnomad EAS AF: 0.439

Gnomad SAS AF: 0.514

Gnomad FIN AF: 0.463

Gnomad MID AF: 0.372

Gnomad NFE AF: 0.460

Gnomad OTH AF: 0.460

GnomAD3 exomes AF: 0.459 AC: 45107 AN: 98168 Hom.: 6450 AF XY: 0.466 AC XY: 16995 AN XY: 36462

Gnomad AFR exome AF: 0.494

Gnomad AMR exome AF: 0.422

Gnomad ASJ exome AF: 0.433

Gnomad EAS exome AF: 0.443

Gnomad SAS exome AF: 0.529

Gnomad FIN exome AF: 0.480

Gnomad NFE exome AF: 0.456

Gnomad OTH exome AF: 0.435

GnomAD4 exome AF: 0.458 AC: 468190 AN: 1022624 Hom.: 72686 Cov.: 34 AF XY: 0.462 AC XY: 150891 AN XY: 326844

Gnomad4 AFR exome AF: 0.500

Gnomad4 AMR exome AF: 0.428

Gnomad4 ASJ exome AF: 0.428

Gnomad4 EAS exome AF: 0.462

Gnomad4 SAS exome AF: 0.521

Gnomad4 FIN exome AF: 0.481

Gnomad4 NFE exome AF: 0.454

Gnomad4 OTH exome AF: 0.453

GnomAD4 genome AF: 0.467 AC: 51356 AN: 109865 Hom.: 8636 Cov.: 22 AF XY: 0.464 AC XY: 14936 AN XY: 32165

Gnomad4 AFR AF: 0.495

Gnomad4 AMR AF: 0.441

Gnomad4 ASJ AF: 0.437

Gnomad4 EAS AF: 0.440

Gnomad4 SAS AF: 0.513

Gnomad4 FIN AF: 0.463

Gnomad4 NFE AF: 0.460

Gnomad4 OTH AF: 0.465

Alfa AF: 0.456 Hom.: 37083

Bravo AF: 0.469

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
Cadd	Benign	0.84
Dann	Benign	0.77
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs6609533; hg19: chrX-47445286; COSMIC: COSV54482649; COSMIC: COSV54482649;