rs5953060

Positions:

• chrX-47585480-G-C

Variant summary

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

The ENST00000218388.9(TIMP1):​c.329-63G>C variant causes a intron 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 ENST00000218388.9 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0200

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=-0.92).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.494 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TIMP1	NM_003254.3	c.329-63G>C		intron_variant		ENST00000218388.9	NP_003245.1
SYN1	NM_006950.3	c.775-7979C>G		intron_variant		ENST00000295987.13	NP_008881.2
SYN1	NM_133499.2	c.775-7979C>G		intron_variant			NP_598006.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TIMP1	ENST00000218388.9	c.329-63G>C		intron_variant		1	NM_003254.3	ENSP00000218388	P1
SYN1	ENST00000295987.13	c.775-7979C>G		intron_variant		2	NM_006950.3	ENSP00000295987	P3

Frequencies

GnomAD3 genomes AF: 0.467 AC: 51895 AN: 111123 Hom.: 8596 Cov.: 23 AF XY: 0.466 AC XY: 15557 AN XY: 33359

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

GnomAD3 exomes AF: 0.469 AC: 67982 AN: 145025 Hom.: 10929 AF XY: 0.479 AC XY: 20781 AN XY: 43373

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 SAS exome AF: 0.533

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

Gnomad4 AFR exome AF: 0.499

Gnomad4 AMR exome AF: 0.432

Gnomad4 ASJ exome AF: 0.428

Gnomad4 EAS exome AF: 0.459

Gnomad4 SAS exome AF: 0.525

Gnomad4 FIN exome AF: 0.480

Gnomad4 NFE exome AF: 0.454

Gnomad4 OTH exome AF: 0.453

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

Gnomad4 AFR AF: 0.494

Gnomad4 AMR AF: 0.441

Gnomad4 ASJ AF: 0.439

Gnomad4 EAS AF: 0.435

Gnomad4 SAS AF: 0.516

Gnomad4 FIN AF: 0.465

Gnomad4 NFE AF: 0.459

Gnomad4 OTH AF: 0.472

Alfa AF: 0.468 Hom.: 4904

Bravo AF: 0.468

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	2.3
DANN	Benign	0.44

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: rs5953060; hg19: chrX-47444879; COSMIC: COSV54482586; COSMIC: COSV54482586;