X-47586642-G-A

Variant names:

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_003254.3(TIMP1):c.575G>A(p.Arg192Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00336 in 1,210,225 control chromosomes in the GnomAD database, including 16 homozygotes. There are 1,230 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0022 ( 1 hom., 63 hem., cov: 25)

Exomes 𝑓: 0.0035 ( 15 hom. 1167 hem. )

Consequence

TIMP1
NM_003254.3 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.0400

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0049708188).

BP6

Variant X-47586642-G-A is Benign according to our data. Variant chrX-47586642-G-A is described in ClinVar as [Benign]. Clinvar id is 720215.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-47586642-G-A is described in Lovd as [Likely_benign].

BS2

High Hemizygotes in GnomAd4 at 63 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TIMP1	NM_003254.3 link	c.575G>A	p.Arg192Gln	missense_variant	Exon 6 of 6	ENST00000218388.9	NP_003245.1	P01033Q6FGX5
SYN1	NM_006950.3 link	c.775-9141C>T		intron_variant	Intron 5 of 12	ENST00000295987.13	NP_008881.2	P17600-1
SYN1	NM_133499.2 link	c.775-9141C>T		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.575G>A	p.Arg192Gln	missense_variant	Exon 6 of 6	1	NM_003254.3	ENSP00000218388.4		P01033
SYN1	ENST00000295987.13 link	c.775-9141C>T		intron_variant	Intron 5 of 12	2	NM_006950.3	ENSP00000295987.7		P17600-1

Frequencies

GnomAD3 genomes

AF:

0.00221

AC:

249

AN:

112736

Hom.:

Cov.:

AF XY:

0.00180

AC XY:

AN XY:

34914

show subpopulations

Gnomad AFR

AF:

0.000903

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000931

Gnomad ASJ

AF:

0.00453

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000358

Gnomad FIN

AF:

0.00176

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00336

Gnomad OTH

AF:

0.00525

GnomAD3 exomes

AF:

0.00232

AC:

423

AN:

182180

Hom.:

AF XY:

0.00245

AC XY:

164

AN XY:

66806

show subpopulations

Gnomad AFR exome

AF:

0.000836

Gnomad AMR exome

AF:

0.00150

Gnomad ASJ exome

AF:

0.00347

Gnomad EAS exome

AF:

0.0000722

Gnomad SAS exome

AF:

0.000472

Gnomad FIN exome

AF:

0.000737

Gnomad NFE exome

AF:

0.00383

Gnomad OTH exome

AF:

0.00244

GnomAD4 exome

AF:

0.00348

AC:

3814

AN:

1097435

Hom.:

Cov.:

AF XY:

0.00322

AC XY:

1167

AN XY:

362949

show subpopulations

Gnomad4 AFR exome

AF:

0.000909

Gnomad4 AMR exome

AF:

0.00136

Gnomad4 ASJ exome

AF:

0.00335

Gnomad4 EAS exome

AF:

0.0000662

Gnomad4 SAS exome

AF:

0.000259

Gnomad4 FIN exome

AF:

0.000780

Gnomad4 NFE exome

AF:

0.00418

Gnomad4 OTH exome

AF:

0.00239

GnomAD4 genome

AF:

0.00221

AC:

249

AN:

112790

Hom.:

Cov.:

AF XY:

0.00180

AC XY:

AN XY:

34978

show subpopulations

Gnomad4 AFR

AF:

0.000901

Gnomad4 AMR

AF:

0.000930

Gnomad4 ASJ

AF:

0.00453

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000359

Gnomad4 FIN

AF:

0.00176

Gnomad4 NFE

AF:

0.00336

Gnomad4 OTH

AF:

0.00518

Alfa

AF:

0.00333

Hom.:

135

Bravo

AF:

0.00195

TwinsUK

AF:

0.00297

AC:

ALSPAC

AF:

0.00554

AC:

ESP6500AA

AF:

0.000782

AC:

ESP6500EA

AF:

0.00282

AC:

ExAC

AF:

0.00241

AC:

293

EpiCase

AF:

0.00289

EpiControl

AF:

0.00433

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Jul 05, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Benign

0.88

DEOGEN2

Uncertain

0.56

D;.

FATHMM_MKL

Benign

0.046

LIST_S2

Benign

0.77

T;T

M_CAP

Uncertain

0.096

MetaRNN

Benign

0.0050

T;T

MetaSVM

Benign

-0.48

MutationAssessor

Benign

0.95

L;.

PrimateAI

Benign

0.21

PROVEAN

Benign

-1.7

N;N

REVEL

Benign

0.28

Sift

Benign

0.14

T;T

Sift4G

Benign

0.50

T;T

Polyphen

0.017

B;.

Vest4

0.054

MVP

0.72

MPC

0.32

ClinPred

0.018

GERP RS

-3.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.37

gMVP

0.45

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