rs192373432

Variant names:

• chrX-47586641-C-T
• rs192373432
• NM_003254.3:c.574C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_003254.3(TIMP1):​c.574C>T​(p.Arg192Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000252 in 1,210,518 control chromosomes in the GnomAD database, including 1 homozygotes. There are 94 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R192Q) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., 3 hem., cov: 24)
  • Exomes 𝑓: 0.00027 (1 hom. 91 hem.)
• Consequence: TIMP1 NM_003254.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.110
• Publications: 5 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: Orphanet, G2P, Ambry Genetics, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)

ENSG00000283743 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0143224895).
• BP6: Variant X-47586641-C-T is Benign according to our data. Variant chrX-47586641-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 732080.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAd4 at 3 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TIMP1	NM_003254.3	MANE Select	c.574C>T	p.Arg192Trp	missense	Exon 6 of 6	NP_003245.1	P01033
	SYN1	NM_006950.3	MANE Select	c.775-9140G>A		intron	N/A	NP_008881.2	P17600-1
	SYN1	NM_133499.2		c.775-9140G>A		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.574C>T	p.Arg192Trp	missense	Exon 6 of 6	ENSP00000218388.4	P01033
	SYN1	ENST00000295987.13	TSL:2 MANE Select	c.775-9140G>A		intron	N/A	ENSP00000295987.7	P17600-1
	SYN1	ENST00000340666.5	TSL:1	c.775-9140G>A		intron	N/A	ENSP00000343206.4	P17600-2

Frequencies

GnomAD3 genomes AF: 0.000124 AC: 14 AN: 112902 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.0000322

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00333

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000188

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000159 AC: 29 AN: 182335 AF XY: 0.000164

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00195

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000122

Gnomad OTH exome AF: 0.000221

GnomAD4 exome AF: 0.000265 AC: 291 AN: 1097563 Hom.: 1 Cov.: 31 AF XY: 0.000251 AC XY: 91 AN XY: 363045

African (AFR) AF: 0.0000379 AC: 1 AN: 26403

American (AMR) AF: 0.00 AC: 0 AN: 35205

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19385

East Asian (EAS) AF: 0.00861 AC: 260 AN: 30204

South Asian (SAS) AF: 0.0000185 AC: 1 AN: 54145

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39867

Middle Eastern (MID) AF: 0.000242 AC: 1 AN: 4131

European-Non Finnish (NFE) AF: 0.0000273 AC: 23 AN: 842140

Other (OTH) AF: 0.000108 AC: 5 AN: 46083

GnomAD4 genome AF: 0.000124 AC: 14 AN: 112955 Hom.: 0 Cov.: 24 AF XY: 0.0000855 AC XY: 3 AN XY: 35101

African (AFR) AF: 0.0000321 AC: 1 AN: 31143

American (AMR) AF: 0.00 AC: 0 AN: 10767

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2656

East Asian (EAS) AF: 0.00334 AC: 12 AN: 3590

South Asian (SAS) AF: 0.00 AC: 0 AN: 2793

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6270

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 219

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53288

Other (OTH) AF: 0.00 AC: 0 AN: 1545

Alfa AF: 0.0000621 Hom.: 0

Bravo AF: 0.0000869

ExAC AF: 0.000189 AC: 23

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.72	D
FATHMM_MKL	Benign	0.081	N
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.43	D
MetaRNN	Benign	0.014	T
MetaSVM	Uncertain	0.12	D
MutationAssessor	Pathogenic	2.9	M
PhyloP100		0.11
PrimateAI	Benign	0.25	T
PROVEAN	Pathogenic	-5.6	D
REVEL	Uncertain	0.43
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.33
MVP		0.89
MPC		0.87
ClinPred		0.33	T
GERP RS		0.82
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.69
gMVP		0.71
Mutation Taster		=70/30	polymorphism

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

Other links and lift over

dbSNP: rs192373432; hg19: chrX-47446040; COSMIC: COSV54484305; COSMIC: COSV54484305;