X-47585264-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_ModerateBP7BS1BS2

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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.17

Publications

11 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=0.112).

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 link	c.261C>T	p.Pro87Pro	synonymous_variant	Exon 4 of 6	ENST00000218388.9	NP_003245.1	P01033Q6FGX5
SYN1	NM_006950.3 link	c.775-7763G>A		intron_variant	Intron 5 of 12	ENST00000295987.13	NP_008881.2	P17600-1
SYN1	NM_133499.2 link	c.775-7763G>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.261C>T	p.Pro87Pro	synonymous_variant	Exon 4 of 6	1	NM_003254.3	ENSP00000218388.4		P01033
SYN1	ENST00000295987.13 link	c.775-7763G>A		intron_variant	Intron 5 of 12	2	NM_006950.3	ENSP00000295987.7		P17600-1

Frequencies

GnomAD3 genomes

AF:

0.0133

AC:

1495

AN:

112126

Hom.:

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.0170

AC XY:

6161

AN XY:

361473

show subpopulations

African (AFR)

AF:

0.00284

AC:

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:

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:

AN:

4119

European-Non Finnish (NFE)

AF:

0.0198

AC:

16665

AN:

840902

Other (OTH)

AF:

0.0162

AC:

747

AN:

45995

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

781

1562

2344

3125

3906

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

630

1260

1890

2520

3150

<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:

0.0133

AC:

1493

AN:

112178

Hom.:

Cov.:

AF XY:

0.0113

AC XY:

387

AN XY:

34342

show subpopulations

African (AFR)

AF:

0.00262

AC:

AN:

30907

American (AMR)

AF:

0.0114

AC:

121

AN:

10635

Ashkenazi Jewish (ASJ)

AF:

0.0365

AC:

AN:

2654

East Asian (EAS)

AF:

0.00

AC:

AN:

3554

South Asian (SAS)

AF:

0.00294

AC:

AN:

2725

European-Finnish (FIN)

AF:

0.00847

AC:

AN:

6139

Middle Eastern (MID)

AF:

0.0415

AC:

AN:

217

European-Non Finnish (NFE)

AF:

0.0206

AC:

1097

AN:

53138

Other (OTH)

AF:

0.0177

AC:

AN:

1526

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

113

170

226

283

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00996

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

(source)

DANN

Uncertain

1.0

PhyloP100

-1.2

PromoterAI

-0.057

Neutral

(source)

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)

0.010

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