rs11551797

Variant names:

• chrX-47586541-C-T
• rs11551797
• NM_003254.3:c.474C>T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_Moderate BP7 BA1

The NM_003254.3(TIMP1):​c.474C>T​(p.Ile158Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0271 in 1,210,261 control chromosomes in the GnomAD database, including 2,074 homozygotes. There are 9,966 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 0.033 (236 hom., 1198 hem., cov: 24)
  • Exomes 𝑓: 0.027 (1838 hom. 8768 hem.)
• Consequence: TIMP1 NM_003254.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.158
• Publications: 16 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 -11 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.149).
• BP7: Synonymous conserved (PhyloP=-0.158 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.26 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003254.3. 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
	TIMP1	NM_003254.3	MANE Select	c.474C>T	p.Ile158Ile	synonymous	Exon 6 of 6	NP_003245.1	P01033
	SYN1	NM_006950.3	MANE Select	c.775-9040G>A		intron	N/A	NP_008881.2	P17600-1
	SYN1	NM_133499.2		c.775-9040G>A		intron	N/A	NP_598006.1	P17600-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TIMP1	ENST00000218388.9	TSL:1 MANE Select	c.474C>T	p.Ile158Ile	synonymous	Exon 6 of 6	ENSP00000218388.4	P01033
	SYN1	ENST00000295987.13	TSL:2 MANE Select	c.775-9040G>A		intron	N/A	ENSP00000295987.7	P17600-1
	SYN1	ENST00000340666.5	TSL:1	c.775-9040G>A		intron	N/A	ENSP00000343206.4	P17600-2

Frequencies

GnomAD3 genomes AF: 0.0326 AC: 3663 AN: 112470 Hom.: 234 Cov.: 24

Gnomad AFR AF: 0.00775

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.172

Gnomad ASJ AF: 0.00113

Gnomad EAS AF: 0.276

Gnomad SAS AF: 0.0119

Gnomad FIN AF: 0.000963

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00939

Gnomad OTH AF: 0.0483

GnomAD2 exomes AF: 0.0721 AC: 13103 AN: 181849 AF XY: 0.0558

Gnomad AFR exome AF: 0.00677

Gnomad AMR exome AF: 0.288

Gnomad ASJ exome AF: 0.000940

Gnomad EAS exome AF: 0.297

Gnomad FIN exome AF: 0.000637

Gnomad NFE exome AF: 0.00840

Gnomad OTH exome AF: 0.0500

GnomAD4 exome AF: 0.0265 AC: 29091 AN: 1097739 Hom.: 1838 Cov.: 31 AF XY: 0.0241 AC XY: 8768 AN XY: 363161

African (AFR) AF: 0.00496 AC: 131 AN: 26400

American (AMR) AF: 0.277 AC: 9717 AN: 35140

Ashkenazi Jewish (ASJ) AF: 0.00119 AC: 23 AN: 19364

East Asian (EAS) AF: 0.241 AC: 7279 AN: 30191

South Asian (SAS) AF: 0.00789 AC: 427 AN: 54122

European-Finnish (FIN) AF: 0.00114 AC: 46 AN: 40392

Middle Eastern (MID) AF: 0.00435 AC: 18 AN: 4136

European-Non Finnish (NFE) AF: 0.0115 AC: 9677 AN: 841926

Other (OTH) AF: 0.0385 AC: 1773 AN: 46068

GnomAD4 genome AF: 0.0326 AC: 3663 AN: 112522 Hom.: 236 Cov.: 24 AF XY: 0.0346 AC XY: 1198 AN XY: 34670

African (AFR) AF: 0.00773 AC: 240 AN: 31050

American (AMR) AF: 0.173 AC: 1842 AN: 10659

Ashkenazi Jewish (ASJ) AF: 0.00113 AC: 3 AN: 2650

East Asian (EAS) AF: 0.275 AC: 965 AN: 3511

South Asian (SAS) AF: 0.0120 AC: 33 AN: 2756

European-Finnish (FIN) AF: 0.000963 AC: 6 AN: 6233

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 219

European-Non Finnish (NFE) AF: 0.00939 AC: 500 AN: 53232

Other (OTH) AF: 0.0483 AC: 74 AN: 1531

Alfa AF: 0.0146 Hom.: 320

Bravo AF: 0.0529

EpiCase AF: 0.00807

EpiControl AF: 0.00872

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	7.1
DANN	Benign	0.83
PhyloP100		-0.16
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)		0.040		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: rs11551797; hg19: chrX-47445940; COSMIC: COSV54482793; COSMIC: COSV54482793;