ENST00000456754.6:c.*473A>G

Variant names:

• chrX-47585887-A-G
• rs6609533
• ENST00000456754.6:c.*473A>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 27 publications found

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]

SYN1 Gene-Disease associations (from GenCC):

• X-linked complex neurodevelopmental disorder

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• epilepsy, X-linked 1, with variable learning disabilities and behavior disorders

  Inheritance: XL Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, G2P, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Orphanet

ENSG00000283743 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.011).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.49 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000456754.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYN1	NM_006950.3	MANE Select	c.775-8386T>C		intron	N/A	NP_008881.2
	TIMP1	NM_003254.3	MANE Select	c.453+220A>G		intron	N/A	NP_003245.1
	SYN1	NM_133499.2		c.775-8386T>C		intron	N/A	NP_598006.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TIMP1	ENST00000456754.6	TSL:1	c.*473A>G		3_prime_UTR	Exon 4 of 4	ENSP00000406671.2
	SYN1	ENST00000295987.13	TSL:2 MANE Select	c.775-8386T>C		intron	N/A	ENSP00000295987.7
	TIMP1	ENST00000218388.9	TSL:1 MANE Select	c.453+220A>G		intron	N/A	ENSP00000218388.4

Frequencies

GnomAD3 genomes AF: 0.467 AC: 51307 AN: 109809 Hom.: 8627 Cov.: 22

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

GnomAD2 exomes AF: 0.459 AC: 45107 AN: 98168 AF XY: 0.466

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 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

African (AFR) AF: 0.500 AC: 12282 AN: 24557

American (AMR) AF: 0.428 AC: 11633 AN: 27203

Ashkenazi Jewish (ASJ) AF: 0.428 AC: 7704 AN: 18007

East Asian (EAS) AF: 0.462 AC: 11803 AN: 25569

South Asian (SAS) AF: 0.521 AC: 25567 AN: 49030

European-Finnish (FIN) AF: 0.481 AC: 11534 AN: 23993

Middle Eastern (MID) AF: 0.440 AC: 1754 AN: 3985

European-Non Finnish (NFE) AF: 0.454 AC: 366358 AN: 807106

Other (OTH) AF: 0.453 AC: 19555 AN: 43174

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

African (AFR) AF: 0.495 AC: 14946 AN: 30175

American (AMR) AF: 0.441 AC: 4579 AN: 10393

Ashkenazi Jewish (ASJ) AF: 0.437 AC: 1147 AN: 2622

East Asian (EAS) AF: 0.440 AC: 1526 AN: 3469

South Asian (SAS) AF: 0.513 AC: 1300 AN: 2533

European-Finnish (FIN) AF: 0.463 AC: 2650 AN: 5723

Middle Eastern (MID) AF: 0.362 AC: 77 AN: 213

European-Non Finnish (NFE) AF: 0.460 AC: 24173 AN: 52583

Other (OTH) AF: 0.465 AC: 697 AN: 1498

Alfa AF: 0.460 Hom.: 50328

Bravo AF: 0.469

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.84
DANN	Benign	0.77
PhyloP100		-0.90
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
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: rs6609533; hg19: chrX-47445286; COSMIC: COSV54482649; COSMIC: COSV54482649;