rs202175145

Variant names:

• chrX-47583513-C-T
• rs202175145
• NM_003254.3:c.98C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Moderate BP6_Moderate BS2

The NM_003254.3(TIMP1):​c.98C>T​(p.Thr33Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000918 in 1,198,221 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000036 (0 hom., 0 hem., cov: 22)
  • Exomes 𝑓: 0.0000064 (0 hom. 2 hem.)
• Consequence: TIMP1 NM_003254.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.595
• Publications: 0 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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.15649152).
• BP6: Variant X-47583513-C-T is Benign according to our data. Variant chrX-47583513-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 3177573.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAdExome4 at 2 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.98C>T	p.Thr33Met	missense	Exon 2 of 6	NP_003245.1	P01033
	SYN1	NM_006950.3	MANE Select	c.775-6012G>A		intron	N/A	NP_008881.2	P17600-1
	SYN1	NM_133499.2		c.775-6012G>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.98C>T	p.Thr33Met	missense	Exon 2 of 6	ENSP00000218388.4	P01033
	TIMP1	ENST00000456754.6	TSL:1	c.98C>T	p.Thr33Met	missense	Exon 2 of 4	ENSP00000406671.2	Q5H9B5
	SYN1	ENST00000295987.13	TSL:2 MANE Select	c.775-6012G>A		intron	N/A	ENSP00000295987.7	P17600-1

Frequencies

GnomAD3 genomes AF: 0.0000357 AC: 4 AN: 112098 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.0000324

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000283

Gnomad SAS AF: 0.000371

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000188

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000177 AC: 3 AN: 169207 AF XY: 0.0000181

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000782

Gnomad FIN exome AF: 0.0000675

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000645 AC: 7 AN: 1086070 Hom.: 0 Cov.: 30 AF XY: 0.00000567 AC XY: 2 AN XY: 353024

African (AFR) AF: 0.0000765 AC: 2 AN: 26143

American (AMR) AF: 0.00 AC: 0 AN: 33899

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18754

East Asian (EAS) AF: 0.0000335 AC: 1 AN: 29810

South Asian (SAS) AF: 0.0000191 AC: 1 AN: 52357

European-Finnish (FIN) AF: 0.0000252 AC: 1 AN: 39729

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4081

European-Non Finnish (NFE) AF: 0.00000120 AC: 1 AN: 835743

Other (OTH) AF: 0.0000220 AC: 1 AN: 45554

GnomAD4 genome AF: 0.0000357 AC: 4 AN: 112151 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 34299

African (AFR) AF: 0.0000324 AC: 1 AN: 30886

American (AMR) AF: 0.00 AC: 0 AN: 10663

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2653

East Asian (EAS) AF: 0.000284 AC: 1 AN: 3527

South Asian (SAS) AF: 0.000372 AC: 1 AN: 2690

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6174

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.0000188 AC: 1 AN: 53124

Other (OTH) AF: 0.00 AC: 0 AN: 1533

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000264

ExAC AF: 0.0000247 AC: 3

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Uncertain	0.041	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	7.6
DANN	Benign	0.91
DEOGEN2	Uncertain	0.61	D
FATHMM_MKL	Benign	0.034	N
LIST_S2	Benign	0.74	T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.16	T
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Benign	1.5	L
PhyloP100		-0.59
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.57	N
REVEL	Benign	0.28
Sift	Benign	0.042	D
Sift4G	Uncertain	0.031	D
Polyphen		0.27	B
Vest4		0.12
MVP		0.67
MPC		0.45
ClinPred		0.038	T
GERP RS		-2.5
Varity_R		0.078
gMVP		0.67
Mutation Taster		=72/28	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs202175145; hg19: chrX-47442912;