X-47585009-G-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_ModerateBP6_ModerateBS2

The NM_003254.3(TIMP1):c.195G>T(p.Met65Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00059 in 1,208,306 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 202 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.00033 ( 0 hom., 8 hem., cov: 23)

Exomes 𝑓: 0.00062 ( 0 hom. 194 hem. )

Consequence

TIMP1
NM_003254.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.271

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 links:

ENSG00000283743 (HGNC:):

ENSG00000283743 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.13798782).

BP6

Variant X-47585009-G-T is Benign according to our data. Variant chrX-47585009-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 2660430.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-47585009-G-T is described in Lovd as [Likely_benign].

BS2

High Hemizygotes in GnomAd4 at 8 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TIMP1	NM_003254.3 link	c.195G>T	p.Met65Ile	missense_variant	Exon 3 of 6	ENST00000218388.9	NP_003245.1	P01033Q6FGX5
SYN1	NM_006950.3 link	c.775-7508C>A		intron_variant	Intron 5 of 12	ENST00000295987.13	NP_008881.2	P17600-1
SYN1	NM_133499.2 link	c.775-7508C>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.195G>T	p.Met65Ile	missense_variant	Exon 3 of 6	1	NM_003254.3	ENSP00000218388.4		P01033
SYN1	ENST00000295987.13 link	c.775-7508C>A		intron_variant	Intron 5 of 12	2	NM_006950.3	ENSP00000295987.7		P17600-1

Frequencies

GnomAD3 genomes

AF:

0.000333

AC:

AN:

111251

Hom.:

Cov.:

AF XY:

0.000239

AC XY:

AN XY:

33427

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000956

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:

0.000679

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000326

AC:

AN:

180814

Hom.:

AF XY:

0.000321

AC XY:

AN XY:

65462

show subpopulations

Gnomad AFR exome

AF:

0.0000769

Gnomad AMR exome

AF:

0.0000735

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000682

Gnomad OTH exome

AF:

0.000224

GnomAD4 exome

AF:

0.000616

AC:

676

AN:

1097055

Hom.:

Cov.:

AF XY:

0.000535

AC XY:

194

AN XY:

362453

show subpopulations

Gnomad4 AFR exome

AF:

0.0000758

Gnomad4 AMR exome

AF:

0.000114

Gnomad4 ASJ exome

AF:

0.0000518

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000768

Gnomad4 OTH exome

AF:

0.000499

GnomAD4 genome

AF:

0.000333

AC:

AN:

111251

Hom.:

Cov.:

AF XY:

0.000239

AC XY:

AN XY:

33427

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000956

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000679

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000218

Hom.:

Bravo

AF:

0.000325

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000595

AC:

ExAC

AF:

0.000313

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Dec 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SYN1: BS2; TIMP1: BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.53

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.24

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Uncertain

0.63

D;T;.;T

FATHMM_MKL

Benign

0.60

LIST_S2

Benign

0.75

T;D;D;D

M_CAP

Benign

0.066

MetaRNN

Benign

0.10

T;T;T;T

MetaSVM

Benign

-0.56

MutationAssessor

Uncertain

2.1

M;.;.;.

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-2.3

N;N;N;N

REVEL

Benign

0.19

Sift

Benign

0.28

T;T;D;T

Sift4G

Benign

0.50

T;T;T;T

Polyphen

0.018

B;.;.;.

Vest4

0.18

MutPred

0.59

Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);.;.;

MVP

0.83

MPC

0.32

ClinPred

0.017

GERP RS

1.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.21

gMVP

0.68

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over