rs751311919

Variant names:

• chrX-47585602-A-C
• rs751311919
• NM_003254.3:c.388A>C

Your query was ambiguous. Multiple possible variants found:

• chrX-47585602-A-C
• chrX-47585602-A-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003254.3(TIMP1):​c.388A>C​(p.Ser130Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000921 in 1,085,255 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.2e-7 (0 hom. 1 hem.)
• Consequence: TIMP1 NM_003254.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.23
• 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: 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14814696).

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.388A>C	p.Ser130Arg	missense	Exon 5 of 6	NP_003245.1	P01033
	SYN1	NM_006950.3	MANE Select	c.775-8101T>G		intron	N/A	NP_008881.2	P17600-1
	SYN1	NM_133499.2		c.775-8101T>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.388A>C	p.Ser130Arg	missense	Exon 5 of 6	ENSP00000218388.4	P01033
	TIMP1	ENST00000456754.6	TSL:1	c.*188A>C		3_prime_UTR	Exon 4 of 4	ENSP00000406671.2	Q5H9B5
	SYN1	ENST00000295987.13	TSL:2 MANE Select	c.775-8101T>G		intron	N/A	ENSP00000295987.7	P17600-1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.0000122 AC: 2 AN: 163485 AF XY: 0.0000195

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000149

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 9.21e-7 AC: 1 AN: 1085255 Hom.: 0 Cov.: 34 AF XY: 0.00000283 AC XY: 1 AN XY: 353323

African (AFR) AF: 0.00 AC: 0 AN: 26258

American (AMR) AF: 0.00 AC: 0 AN: 34351

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18393

East Asian (EAS) AF: 0.0000332 AC: 1 AN: 30095

South Asian (SAS) AF: 0.00 AC: 0 AN: 51140

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39935

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4074

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 835383

Other (OTH) AF: 0.00 AC: 0 AN: 45626

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000248 AC: 3

ClinVar

ClinVar submissions

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	0.23
BayesDel_addAF	Benign	-0.080	T
BayesDel_noAF	Benign	-0.090
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.61	D
FATHMM_MKL	Benign	0.49	N
LIST_S2	Benign	0.53	T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.15	T
MetaSVM	Uncertain	0.074	D
MutationAssessor	Benign	1.7	L
PhyloP100		2.2
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.51
Sift	Uncertain	0.012	D
Sift4G	Benign	0.52	T
Polyphen		0.99	D
Vest4		0.23
MVP		0.68
MPC		0.35
ClinPred		0.087	T
GERP RS		4.1
PromoterAI		-0.037	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.42
gMVP		0.71
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs751311919; hg19: chrX-47445001;