X-47585009-G-A

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_003254.3(TIMP1):c.195G>A(p.Met65Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000384 in 1,208,306 control chromosomes in the GnomAD database, including 2 homozygotes. There are 133 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

Frequency

Genomes: 𝑓 0.00024 ( 1 hom., 6 hem., cov: 23)

Exomes 𝑓: 0.00040 ( 1 hom. 127 hem. )

Consequence

TIMP1
NM_003254.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.271

Publications

0 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: 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

SYN1 links:

ENSG00000283743 (HGNC:):

ENSG00000283743 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.16863927).

BS2

High Hemizygotes in GnomAd4 at 6 gene

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TIMP1	NM_003254.3	MANE Select	c.195G>A	p.Met65Ile	missense	Exon 3 of 6	NP_003245.1	P01033
SYN1	NM_006950.3	MANE Select	c.775-7508C>T		intron	N/A	NP_008881.2	P17600-1
SYN1	NM_133499.2		c.775-7508C>T		intron	N/A	NP_598006.1	P17600-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TIMP1	ENST00000218388.9	TSL:1 MANE Select	c.195G>A	p.Met65Ile	missense	Exon 3 of 6	ENSP00000218388.4	P01033
TIMP1	ENST00000456754.6	TSL:1	c.195G>A	p.Met65Ile	missense	Exon 3 of 4	ENSP00000406671.2	Q5H9B5
SYN1	ENST00000295987.13	TSL:2 MANE Select	c.775-7508C>T		intron	N/A	ENSP00000295987.7	P17600-1

Frequencies

GnomAD3 genomes

AF:

0.000243

AC:

AN:

111251

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000982

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000434

Gnomad OTH

AF:

0.000661

GnomAD2 exomes

AF:

0.000227

AC:

AN:

180814

AF XY:

0.000260

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000252

Gnomad NFE exome

AF:

0.000422

Gnomad OTH exome

AF:

0.000673

GnomAD4 exome

AF:

0.000398

AC:

437

AN:

1097055

Hom.:

Cov.:

AF XY:

0.000350

AC XY:

127

AN XY:

362453

show subpopulations

African (AFR)

AF:

0.0000758

AC:

AN:

26388

American (AMR)

AF:

0.00

AC:

AN:

35143

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19313

East Asian (EAS)

AF:

0.00

AC:

AN:

30198

South Asian (SAS)

AF:

0.00

AC:

AN:

53903

European-Finnish (FIN)

AF:

0.000519

AC:

AN:

40479

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4134

European-Non Finnish (NFE)

AF:

0.000475

AC:

400

AN:

841442

Other (OTH)

AF:

0.000304

AC:

AN:

46055

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.000243

AC:

AN:

111251

Hom.:

Cov.:

AF XY:

0.000179

AC XY:

AN XY:

33427

show subpopulations

African (AFR)

AF:

0.0000982

AC:

AN:

30549

American (AMR)

AF:

0.00

AC:

AN:

10456

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2634

East Asian (EAS)

AF:

0.00

AC:

AN:

3565

South Asian (SAS)

AF:

0.00

AC:

AN:

2632

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5934

Middle Eastern (MID)

AF:

0.00

AC:

AN:

238

European-Non Finnish (NFE)

AF:

0.000434

AC:

AN:

53047

Other (OTH)

AF:

0.000661

AC:

AN:

1513

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.000145

Hom.:

Bravo

AF:

0.000215

ExAC

AF:

0.000231

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.53

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.24

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Uncertain

0.63

FATHMM_MKL

Benign

0.54

LIST_S2

Benign

0.75

M_CAP

Benign

0.066

MetaRNN

Benign

0.13

MetaSVM

Benign

-0.56

MutationAssessor

Uncertain

2.1

PhyloP100

0.27

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-2.3

REVEL

Benign

0.23

Sift

Benign

0.28

Sift4G

Benign

0.50

Polyphen

0.018

Vest4

0.18

MutPred

0.59

Gain of sheet (P = 0.0827)

MVP

0.83

MPC

0.32

ClinPred

0.033

GERP RS

1.1

PromoterAI

-0.049

Neutral

(source)

Varity_R

0.21

gMVP

0.68

Mutation Taster

=163/37

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over