rs369537887

Variant names:

• chrX-47583437-G-A
• rs369537887
• NM_003254.3:c.22G>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_003254.3(TIMP1):​c.22G>A​(p.Ala8Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000349 in 1,204,747 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 19 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., 1 hem., cov: 22)
  • Exomes 𝑓: 0.000036 (0 hom. 18 hem.)
• Consequence: TIMP1 NM_003254.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.766
• Publications: 4 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=0.05483681).
• BS2: High Hemizygotes in GnomAdExome4 at 18 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.22G>A	p.Ala8Thr	missense	Exon 2 of 6	NP_003245.1	P01033
	SYN1	NM_006950.3	MANE Select	c.775-5936C>T		intron	N/A	NP_008881.2	P17600-1
	SYN1	NM_133499.2		c.775-5936C>T		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.22G>A	p.Ala8Thr	missense	Exon 2 of 6	ENSP00000218388.4	P01033
	TIMP1	ENST00000456754.6	TSL:1	c.22G>A	p.Ala8Thr	missense	Exon 2 of 4	ENSP00000406671.2	Q5H9B5
	SYN1	ENST00000295987.13	TSL:2 MANE Select	c.775-5936C>T		intron	N/A	ENSP00000295987.7	P17600-1

Frequencies

GnomAD3 genomes AF: 0.0000271 AC: 3 AN: 110737 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00114

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000734 AC: 13 AN: 177177 AF XY: 0.0000482

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00137

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000376

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000356 AC: 39 AN: 1094010 Hom.: 0 Cov.: 30 AF XY: 0.0000500 AC XY: 18 AN XY: 360042

African (AFR) AF: 0.00 AC: 0 AN: 26318

American (AMR) AF: 0.00 AC: 0 AN: 34960

Ashkenazi Jewish (ASJ) AF: 0.00156 AC: 30 AN: 19278

East Asian (EAS) AF: 0.000100 AC: 3 AN: 29994

South Asian (SAS) AF: 0.00 AC: 0 AN: 53609

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39538

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4128

European-Non Finnish (NFE) AF: 0.00000357 AC: 3 AN: 840224

Other (OTH) AF: 0.0000653 AC: 3 AN: 45961

GnomAD4 genome AF: 0.0000271 AC: 3 AN: 110737 Hom.: 0 Cov.: 22 AF XY: 0.0000304 AC XY: 1 AN XY: 32941

African (AFR) AF: 0.00 AC: 0 AN: 30380

American (AMR) AF: 0.00 AC: 0 AN: 10461

Ashkenazi Jewish (ASJ) AF: 0.00114 AC: 3 AN: 2635

East Asian (EAS) AF: 0.00 AC: 0 AN: 3493

South Asian (SAS) AF: 0.00 AC: 0 AN: 2606

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5956

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 232

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 52807

Other (OTH) AF: 0.00 AC: 0 AN: 1498

Alfa AF: 0.000304 Hom.: 2

Bravo AF: 0.0000264

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.0000577 AC: 7

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

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	0.093
BayesDel_addAF	Uncertain	0.019	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	11
DANN	Benign	0.95
DEOGEN2	Benign	0.15	T
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.66	T
M_CAP	Uncertain	0.086	D
MetaRNN	Benign	0.055	T
MetaSVM	Uncertain	0.21	D
MutationAssessor	Benign	1.6	L
PhyloP100		0.77
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.27
Sift	Uncertain	0.018	D
Sift4G	Benign	0.15	T
Polyphen		0.89	P
Vest4		0.15
MVP		0.81
MPC		0.34
ClinPred		0.069	T
GERP RS		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.12
gMVP		0.62
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs369537887; hg19: chrX-47442836;