X-47585586-T-C

Position:

chrX-47585586-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_003254.3(TIMP1):c.372T>C(p.Phe124Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.461 in 1,194,351 control chromosomes in the GnomAD database, including 85,727 homozygotes. There are 178,638 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.46 ( 8491 hom., 14986 hem., cov: 22)

Exomes 𝑓: 0.46 ( 77236 hom. 163652 hem. )

Consequence

TIMP1
NM_003254.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.721

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BP6

Variant X-47585586-T-C is Benign according to our data. Variant chrX-47585586-T-C is described in ClinVar as [Benign]. Clinvar id is 1165693.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-47585586-T-C is described in Lovd as [Likely_benign].

BP7

Synonymous conserved (PhyloP=-0.721 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.493 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TIMP1	NM_003254.3 link	c.372T>C	p.Phe124Phe	synonymous_variant	5/6	ENST00000218388.9	NP_003245.1	P01033Q6FGX5
SYN1	NM_006950.3 link	c.775-8085A>G		intron_variant		ENST00000295987.13	NP_008881.2	P17600-1
SYN1	NM_133499.2 link	c.775-8085A>G		intron_variant			NP_598006.1	P17600-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TIMP1	ENST00000218388.9 link	c.372T>C	p.Phe124Phe	synonymous_variant	5/6	1	NM_003254.3	ENSP00000218388.4		P01033
SYN1	ENST00000295987.13 link	c.775-8085A>G		intron_variant		2	NM_006950.3	ENSP00000295987.7		P17600-1

Frequencies

GnomAD3 genomes

AF:

0.463

AC:

51051

AN:

110273

Hom.:

8482

Cov.:

AF XY:

0.459

AC XY:

14948

AN XY:

32549

show subpopulations

Gnomad AFR

AF:

0.472

Gnomad AMI

AF:

0.400

Gnomad AMR

AF:

0.438

Gnomad ASJ

AF:

0.441

Gnomad EAS

AF:

0.438

Gnomad SAS

AF:

0.517

Gnomad FIN

AF:

0.468

Gnomad MID

AF:

0.366

Gnomad NFE

AF:

0.464

Gnomad OTH

AF:

0.466

GnomAD3 exomes

AF:

0.463

AC:

74441

AN:

160949

Hom.:

11891

AF XY:

0.469

AC XY:

22946

AN XY:

48961

show subpopulations

Gnomad AFR exome

AF:

0.473

Gnomad AMR exome

AF:

0.423

Gnomad ASJ exome

AF:

0.428

Gnomad EAS exome

AF:

0.444

Gnomad SAS exome

AF:

0.525

Gnomad FIN exome

AF:

0.484

Gnomad NFE exome

AF:

0.466

Gnomad OTH exome

AF:

0.435

GnomAD4 exome

AF:

0.460

AC:

499057

AN:

1084023

Hom.:

77236

Cov.:

AF XY:

0.464

AC XY:

163652

AN XY:

352501

show subpopulations

Gnomad4 AFR exome

AF:

0.476

Gnomad4 AMR exome

AF:

0.429

Gnomad4 ASJ exome

AF:

0.430

Gnomad4 EAS exome

AF:

0.460

Gnomad4 SAS exome

AF:

0.524

Gnomad4 FIN exome

AF:

0.484

Gnomad4 NFE exome

AF:

0.457

Gnomad4 OTH exome

AF:

0.455

GnomAD4 genome

AF:

0.463

AC:

51098

AN:

110328

Hom.:

8491

Cov.:

AF XY:

0.459

AC XY:

14986

AN XY:

32614

show subpopulations

Gnomad4 AFR

AF:

0.472

Gnomad4 AMR

AF:

0.438

Gnomad4 ASJ

AF:

0.441

Gnomad4 EAS

AF:

0.439

Gnomad4 SAS

AF:

0.516

Gnomad4 FIN

AF:

0.468

Gnomad4 NFE

AF:

0.464

Gnomad4 OTH

AF:

0.471

Alfa

AF:

0.460

Hom.:

22817

Bravo

AF:

0.464

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Epilepsy, X-linked 1, with variable learning disabilities and behavior disorders

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

7.2

DANN

Benign

0.59

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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

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