rs149986790

Variant names:

• chrX-47586642-G-A
• rs149986790
• NM_003254.3:c.575G>A

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.575G>A​(p.Arg192Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00336 in 1,210,225 control chromosomes in the GnomAD database, including 16 homozygotes. There are 1,230 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R192W) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0022 (1 hom., 63 hem., cov: 25)
  • Exomes 𝑓: 0.0035 (15 hom. 1167 hem.)
• Consequence: TIMP1 NM_003254.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.0400
• Publications: 3 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=0.0049708188).
• BP6: Variant X-47586642-G-A is Benign according to our data. Variant chrX-47586642-G-A is described in ClinVar as Benign. ClinVar VariationId is 720215.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAd4 at 63 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.575G>A	p.Arg192Gln	missense	Exon 6 of 6	NP_003245.1	P01033
	SYN1	NM_006950.3	MANE Select	c.775-9141C>T		intron	N/A	NP_008881.2	P17600-1
	SYN1	NM_133499.2		c.775-9141C>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.575G>A	p.Arg192Gln	missense	Exon 6 of 6	ENSP00000218388.4	P01033
	SYN1	ENST00000295987.13	TSL:2 MANE Select	c.775-9141C>T		intron	N/A	ENSP00000295987.7	P17600-1
	SYN1	ENST00000340666.5	TSL:1	c.775-9141C>T		intron	N/A	ENSP00000343206.4	P17600-2

Frequencies

GnomAD3 genomes AF: 0.00221 AC: 249 AN: 112736 Hom.: 1 Cov.: 25

Gnomad AFR AF: 0.000903

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000931

Gnomad ASJ AF: 0.00453

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000358

Gnomad FIN AF: 0.00176

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00336

Gnomad OTH AF: 0.00525

GnomAD2 exomes AF: 0.00232 AC: 423 AN: 182180 AF XY: 0.00245

Gnomad AFR exome AF: 0.000836

Gnomad AMR exome AF: 0.00150

Gnomad ASJ exome AF: 0.00347

Gnomad EAS exome AF: 0.0000722

Gnomad FIN exome AF: 0.000737

Gnomad NFE exome AF: 0.00383

Gnomad OTH exome AF: 0.00244

GnomAD4 exome AF: 0.00348 AC: 3814 AN: 1097435 Hom.: 15 Cov.: 31 AF XY: 0.00322 AC XY: 1167 AN XY: 362949

African (AFR) AF: 0.000909 AC: 24 AN: 26402

American (AMR) AF: 0.00136 AC: 48 AN: 35204

Ashkenazi Jewish (ASJ) AF: 0.00335 AC: 65 AN: 19385

East Asian (EAS) AF: 0.0000662 AC: 2 AN: 30204

South Asian (SAS) AF: 0.000259 AC: 14 AN: 54145

European-Finnish (FIN) AF: 0.000780 AC: 31 AN: 39758

Middle Eastern (MID) AF: 0.000242 AC: 1 AN: 4126

European-Non Finnish (NFE) AF: 0.00418 AC: 3519 AN: 842126

Other (OTH) AF: 0.00239 AC: 110 AN: 46085

GnomAD4 genome AF: 0.00221 AC: 249 AN: 112790 Hom.: 1 Cov.: 25 AF XY: 0.00180 AC XY: 63 AN XY: 34978

African (AFR) AF: 0.000901 AC: 28 AN: 31086

American (AMR) AF: 0.000930 AC: 10 AN: 10750

Ashkenazi Jewish (ASJ) AF: 0.00453 AC: 12 AN: 2651

East Asian (EAS) AF: 0.00 AC: 0 AN: 3579

South Asian (SAS) AF: 0.000359 AC: 1 AN: 2786

European-Finnish (FIN) AF: 0.00176 AC: 11 AN: 6247

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

European-Non Finnish (NFE) AF: 0.00336 AC: 179 AN: 53244

Other (OTH) AF: 0.00518 AC: 8 AN: 1544

Alfa AF: 0.00311 Hom.: 136

Bravo AF: 0.00195

TwinsUK AF: 0.00297 AC: 11

ALSPAC AF: 0.00554 AC: 16

ESP6500AA AF: 0.000782 AC: 3

ESP6500EA AF: 0.00282 AC: 19

ExAC AF: 0.00241 AC: 293

EpiCase AF: 0.00289

EpiControl AF: 0.00433

ClinVar

ClinVar submissions as Germline

Significance: 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	0.078
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	13
DANN	Benign	0.88
DEOGEN2	Uncertain	0.56	D
FATHMM_MKL	Benign	0.046	N
LIST_S2	Benign	0.77	T
M_CAP	Uncertain	0.096	D
MetaRNN	Benign	0.0050	T
MetaSVM	Benign	-0.48	T
MutationAssessor	Benign	0.95	L
PhyloP100		-0.040
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.28
Sift	Benign	0.14	T
Sift4G	Benign	0.50	T
Polyphen		0.017	B
Vest4		0.054
MVP		0.72
MPC		0.32
ClinPred		0.018	T
GERP RS		-3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.37
gMVP		0.45
Mutation Taster		=84/16	polymorphism (auto)

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: rs149986790; hg19: chrX-47446041; COSMIC: COSV54482840; COSMIC: COSV54482840;