chrX-47585586-T-C

Variant names:

• chrX-47585586-T-C
• rs4898
• NM_003254.3:c.372T>C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.721
• Publications: 100 publications found

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]

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

ENSG00000283743 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (REVEL=0.018).
• BP6: Variant X-47585586-T-C is Benign according to our data. Variant chrX-47585586-T-C is described in ClinVar as Benign. ClinVar VariationId is 1165693.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TIMP1	NM_003254.3	MANE Select	c.372T>C	p.Phe124Phe	synonymous	Exon 5 of 6	NP_003245.1	P01033
	SYN1	NM_006950.3	MANE Select	c.775-8085A>G		intron	N/A	NP_008881.2	P17600-1
	SYN1	NM_133499.2		c.775-8085A>G		intron	N/A	NP_598006.1	P17600-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TIMP1	ENST00000218388.9	TSL:1 MANE Select	c.372T>C	p.Phe124Phe	synonymous	Exon 5 of 6	ENSP00000218388.4	P01033
	TIMP1	ENST00000456754.6	TSL:1	c.*172T>C		3_prime_UTR	Exon 4 of 4	ENSP00000406671.2	Q5H9B5
	SYN1	ENST00000295987.13	TSL:2 MANE Select	c.775-8085A>G		intron	N/A	ENSP00000295987.7	P17600-1

Frequencies

GnomAD3 genomes AF: 0.463 AC: 51051 AN: 110273 Hom.: 8482 Cov.: 22

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

GnomAD2 exomes AF: 0.463 AC: 74441 AN: 160949 AF XY: 0.469

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 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.: 36 AF XY: 0.464 AC XY: 163652 AN XY: 352501

African (AFR) AF: 0.476 AC: 12502 AN: 26241

American (AMR) AF: 0.429 AC: 14601 AN: 34032

Ashkenazi Jewish (ASJ) AF: 0.430 AC: 7969 AN: 18532

East Asian (EAS) AF: 0.460 AC: 13785 AN: 29980

South Asian (SAS) AF: 0.524 AC: 27060 AN: 51616

European-Finnish (FIN) AF: 0.484 AC: 19313 AN: 39864

Middle Eastern (MID) AF: 0.437 AC: 1779 AN: 4067

European-Non Finnish (NFE) AF: 0.457 AC: 381349 AN: 834149

Other (OTH) AF: 0.455 AC: 20699 AN: 45542

GnomAD4 genome AF: 0.463 AC: 51098 AN: 110328 Hom.: 8491 Cov.: 22 AF XY: 0.459 AC XY: 14986 AN XY: 32614

African (AFR) AF: 0.472 AC: 14323 AN: 30354

American (AMR) AF: 0.438 AC: 4611 AN: 10525

Ashkenazi Jewish (ASJ) AF: 0.441 AC: 1156 AN: 2621

East Asian (EAS) AF: 0.439 AC: 1521 AN: 3467

South Asian (SAS) AF: 0.516 AC: 1316 AN: 2548

European-Finnish (FIN) AF: 0.468 AC: 2753 AN: 5885

Middle Eastern (MID) AF: 0.355 AC: 76 AN: 214

European-Non Finnish (NFE) AF: 0.464 AC: 24368 AN: 52546

Other (OTH) AF: 0.471 AC: 708 AN: 1503

Alfa AF: 0.459 Hom.: 33354

Bravo AF: 0.464

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Epilepsy, X-linked 1, with variable learning disabilities and behavior disorders (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	7.2
DANN	Benign	0.59
PhyloP100		-0.72
PromoterAI		0.091	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4898; hg19: chrX-47444985; COSMIC: COSV54483037; COSMIC: COSV54483037;