NM_003254.3:c.261C>T

Variant names:

• chrX-47585264-C-T
• rs1043428
• NM_003254.3:c.261C>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP7 BS1 BS2

The NM_003254.3(TIMP1):​c.261C>T​(p.Pro87Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0172 in 1,208,079 control chromosomes in the GnomAD database, including 160 homozygotes. There are 6,548 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 0.013 (19 hom., 387 hem., cov: 23)
  • Exomes 𝑓: 0.018 (141 hom. 6161 hem.)
• Consequence: TIMP1 NM_003254.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.17
• Publications: 11 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.112).
• BP7: Synonymous conserved (PhyloP=-1.17 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0133 (1493/112178) while in subpopulation NFE AF = 0.0206 (1097/53138). AF 95% confidence interval is 0.0196. There are 19 homozygotes in GnomAd4. There are 387 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 19 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TIMP1	NM_003254.3	c.261C>T	p.Pro87Pro	synonymous_variant	Exon 4 of 6	ENST00000218388.9	NP_003245.1
SYN1	NM_006950.3	c.775-7763G>A		intron_variant	Intron 5 of 12	ENST00000295987.13	NP_008881.2
SYN1	NM_133499.2	c.775-7763G>A		intron_variant	Intron 5 of 12		NP_598006.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TIMP1	ENST00000218388.9	c.261C>T	p.Pro87Pro	synonymous_variant	Exon 4 of 6	1	NM_003254.3	ENSP00000218388.4
SYN1	ENST00000295987.13	c.775-7763G>A		intron_variant	Intron 5 of 12	2	NM_006950.3	ENSP00000295987.7

Frequencies

GnomAD3 genomes AF: 0.0133 AC: 1495 AN: 112126 Hom.: 19 Cov.: 23

Gnomad AFR AF: 0.00263

Gnomad AMI AF: 0.00146

Gnomad AMR AF: 0.0114

Gnomad ASJ AF: 0.0365

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00293

Gnomad FIN AF: 0.00847

Gnomad MID AF: 0.0378

Gnomad NFE AF: 0.0207

Gnomad OTH AF: 0.0179

GnomAD2 exomes AF: 0.0135 AC: 2418 AN: 178468 AF XY: 0.0135

Gnomad AFR exome AF: 0.00270

Gnomad AMR exome AF: 0.00936

Gnomad ASJ exome AF: 0.0421

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00826

Gnomad NFE exome AF: 0.0196

Gnomad OTH exome AF: 0.0161

GnomAD4 exome AF: 0.0176 AC: 19292 AN: 1095901 Hom.: 141 Cov.: 32 AF XY: 0.0170 AC XY: 6161 AN XY: 361473

African (AFR) AF: 0.00284 AC: 75 AN: 26370

American (AMR) AF: 0.00969 AC: 339 AN: 34987

Ashkenazi Jewish (ASJ) AF: 0.0395 AC: 760 AN: 19217

East Asian (EAS) AF: 0.00 AC: 0 AN: 30183

South Asian (SAS) AF: 0.00447 AC: 240 AN: 53674

European-Finnish (FIN) AF: 0.00927 AC: 375 AN: 40454

Middle Eastern (MID) AF: 0.0221 AC: 91 AN: 4119

European-Non Finnish (NFE) AF: 0.0198 AC: 16665 AN: 840902

Other (OTH) AF: 0.0162 AC: 747 AN: 45995

GnomAD4 genome AF: 0.0133 AC: 1493 AN: 112178 Hom.: 19 Cov.: 23 AF XY: 0.0113 AC XY: 387 AN XY: 34342

African (AFR) AF: 0.00262 AC: 81 AN: 30907

American (AMR) AF: 0.0114 AC: 121 AN: 10635

Ashkenazi Jewish (ASJ) AF: 0.0365 AC: 97 AN: 2654

East Asian (EAS) AF: 0.00 AC: 0 AN: 3554

South Asian (SAS) AF: 0.00294 AC: 8 AN: 2725

European-Finnish (FIN) AF: 0.00847 AC: 52 AN: 6139

Middle Eastern (MID) AF: 0.0415 AC: 9 AN: 217

European-Non Finnish (NFE) AF: 0.0206 AC: 1097 AN: 53138

Other (OTH) AF: 0.0177 AC: 27 AN: 1526

Alfa AF: 0.00996 Hom.: 119

Bravo AF: 0.0135

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	5.5
DANN	Uncertain	1.0
PhyloP100		-1.2
PromoterAI		-0.057	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1043428; hg19: chrX-47444663; COSMIC: COSV54483093; COSMIC: COSV54483093;