chrX-47585480-G-C

Variant names:

• chrX-47585480-G-C
• rs5953060
• ENST00000456754.6:c.*66G>C

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The ENST00000456754.6(TIMP1):​c.*66G>C 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 1,188,928 control chromosomes in the GnomAD database, including 84,550 homozygotes. There are 177,936 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 (8605 hom., 15594 hem., cov: 23)
  • Exomes 𝑓: 0.46 (75945 hom. 162342 hem.)
• Consequence: TIMP1 ENST00000456754.6 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0200
• Publications: 12 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: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, Laboratory for Molecular Medicine, G2P
• intellectual disability, X-linked 50

  Inheritance: XL Classification: STRONG Submitted by: PanelApp Australia

ENSG00000283743 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.028).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.494 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYN1	NM_006950.3	MANE Select	c.775-7979C>G		intron	N/A	NP_008881.2	P17600-1
	TIMP1	NM_003254.3	MANE Select	c.329-63G>C		intron	N/A	NP_003245.1	P01033
	SYN1	NM_133499.2		c.775-7979C>G		intron	N/A	NP_598006.1	P17600-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TIMP1	ENST00000456754.6	TSL:1	c.*66G>C		3_prime_UTR	Exon 4 of 4	ENSP00000406671.2	Q5H9B5
	SYN1	ENST00000295987.13	TSL:2 MANE Select	c.775-7979C>G		intron	N/A	ENSP00000295987.7	P17600-1
	TIMP1	ENST00000218388.9	TSL:1 MANE Select	c.329-63G>C		intron	N/A	ENSP00000218388.4	P01033

Frequencies

GnomAD3 genomes AF: 0.467 AC: 51895 AN: 111123 Hom.: 8596 Cov.: 23

Gnomad AFR AF: 0.494

Gnomad AMI AF: 0.399

Gnomad AMR AF: 0.441

Gnomad ASJ AF: 0.439

Gnomad EAS AF: 0.435

Gnomad SAS AF: 0.517

Gnomad FIN AF: 0.465

Gnomad MID AF: 0.381

Gnomad NFE AF: 0.459

Gnomad OTH AF: 0.467

GnomAD2 exomes AF: 0.469 AC: 67982 AN: 145025 AF XY: 0.479

Gnomad AFR exome AF: 0.502

Gnomad AMR exome AF: 0.427

Gnomad ASJ exome AF: 0.434

Gnomad EAS exome AF: 0.450

Gnomad FIN exome AF: 0.482

Gnomad NFE exome AF: 0.469

Gnomad OTH exome AF: 0.435

GnomAD4 exome AF: 0.458 AC: 493963 AN: 1077752 Hom.: 75945 Cov.: 39 AF XY: 0.463 AC XY: 162342 AN XY: 350774

African (AFR) AF: 0.499 AC: 13039 AN: 26107

American (AMR) AF: 0.432 AC: 13781 AN: 31919

Ashkenazi Jewish (ASJ) AF: 0.428 AC: 8090 AN: 18891

East Asian (EAS) AF: 0.459 AC: 13529 AN: 29497

South Asian (SAS) AF: 0.525 AC: 27270 AN: 51945

European-Finnish (FIN) AF: 0.480 AC: 18771 AN: 39066

Middle Eastern (MID) AF: 0.441 AC: 1800 AN: 4085

European-Non Finnish (NFE) AF: 0.454 AC: 377140 AN: 830931

Other (OTH) AF: 0.453 AC: 20543 AN: 45311

GnomAD4 genome AF: 0.467 AC: 51941 AN: 111176 Hom.: 8605 Cov.: 23 AF XY: 0.467 AC XY: 15594 AN XY: 33422

African (AFR) AF: 0.494 AC: 15125 AN: 30590

American (AMR) AF: 0.441 AC: 4672 AN: 10599

Ashkenazi Jewish (ASJ) AF: 0.439 AC: 1156 AN: 2636

East Asian (EAS) AF: 0.435 AC: 1515 AN: 3479

South Asian (SAS) AF: 0.516 AC: 1381 AN: 2675

European-Finnish (FIN) AF: 0.465 AC: 2791 AN: 6002

Middle Eastern (MID) AF: 0.372 AC: 80 AN: 215

European-Non Finnish (NFE) AF: 0.459 AC: 24240 AN: 52797

Other (OTH) AF: 0.472 AC: 714 AN: 1513

Alfa AF: 0.468 Hom.: 4904

Bravo AF: 0.468

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	2.3
DANN	Benign	0.44
PhyloP100		0.020
PromoterAI		-0.033	Neutral
Mutation Taster		=99/1	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: rs5953060; hg19: chrX-47444879; COSMIC: COSV54482586; COSMIC: COSV54482586;