NM_003254.3:c.474C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_ModerateBP7BA1

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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.158

Publications

16 publications found

Variant links:

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]

TIMP1 links:

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

SYN1 links:

ENSG00000283743 (HGNC:):

ENSG00000283743 links:

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ACMG classification

Classification was made for transcript

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TIMP1	NM_003254.3 link	c.474C>T	p.Ile158Ile	synonymous_variant	Exon 6 of 6	ENST00000218388.9	NP_003245.1	P01033Q6FGX5
SYN1	NM_006950.3 link	c.775-9040G>A		intron_variant	Intron 5 of 12	ENST00000295987.13	NP_008881.2	P17600-1
SYN1	NM_133499.2 link	c.775-9040G>A		intron_variant	Intron 5 of 12		NP_598006.1	P17600-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TIMP1	ENST00000218388.9 link	c.474C>T	p.Ile158Ile	synonymous_variant	Exon 6 of 6	1	NM_003254.3	ENSP00000218388.4		P01033
SYN1	ENST00000295987.13 link	c.775-9040G>A		intron_variant	Intron 5 of 12	2	NM_006950.3	ENSP00000295987.7		P17600-1

Frequencies

GnomAD3 genomes

AF:

0.0326

AC:

3663

AN:

112470

Hom.:

234

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.0241

AC XY:

8768

AN XY:

363161

show subpopulations

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:

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:

AN:

40392

Middle Eastern (MID)

AF:

0.00435

AC:

AN:

4136

European-Non Finnish (NFE)

AF:

0.0115

AC:

9677

AN:

841926

Other (OTH)

AF:

0.0385

AC:

1773

AN:

46068

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

949

1897

2846

3794

4743

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

636

1272

1908

2544

3180

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0326

AC:

3663

AN:

112522

Hom.:

236

Cov.:

AF XY:

0.0346

AC XY:

1198

AN XY:

34670

show subpopulations

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:

AN:

2650

East Asian (EAS)

AF:

0.275

AC:

965

AN:

3511

South Asian (SAS)

AF:

0.0120

AC:

AN:

2756

European-Finnish (FIN)

AF:

0.000963

AC:

AN:

6233

Middle Eastern (MID)

AF:

0.00

AC:

AN:

219

European-Non Finnish (NFE)

AF:

0.00939

AC:

500

AN:

53232

Other (OTH)

AF:

0.0483

AC:

AN:

1531

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

106

212

318

424

530

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

126

168

210

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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 v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.35

CADD

Benign

7.1

(source)

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)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over