X-47585602-A-C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 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. 12/20 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

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]

ENSG00000283743 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TIMP1	NM_003254.3	c.388A>C	p.Ser130Arg	missense_variant	Exon 5 of 6	ENST00000218388.9	NP_003245.1
SYN1	NM_006950.3	c.775-8101T>G		intron_variant	Intron 5 of 12	ENST00000295987.13	NP_008881.2
SYN1	NM_133499.2	c.775-8101T>G		intron_variant	Intron 5 of 12		NP_598006.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TIMP1	ENST00000218388.9	c.388A>C	p.Ser130Arg	missense_variant	Exon 5 of 6	1	NM_003254.3	ENSP00000218388.4
SYN1	ENST00000295987.13	c.775-8101T>G		intron_variant	Intron 5 of 12	2	NM_006950.3	ENSP00000295987.7

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.0000122 AC: 2 AN: 163485 Hom.: 0 AF XY: 0.0000195 AC XY: 1 AN XY: 51331

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 SAS exome AF: 0.00

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000332

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

Bravo AF: 0.00000378

ExAC AF: 0.0000248 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 28, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.388A>C (p.S130R) alteration is located in exon 5 (coding exon 4) of the TIMP1 gene. This alteration results from a A to C substitution at nucleotide position 388, causing the serine (S) at amino acid position 130 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

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;T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.15	T;T
MetaSVM	Uncertain	0.074	D
MutationAssessor	Benign	1.7	L;.
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.5	N;N
REVEL	Uncertain	0.51
Sift	Uncertain	0.012	D;T
Sift4G	Benign	0.52	T;T
Polyphen		0.99	D;.
Vest4		0.23
MVP		0.68
MPC		0.35
ClinPred		0.087	T
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.42
gMVP		0.71

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

Publications

LitVar

Other links and lift over

dbSNP: rs751311919; hg19: chrX-47445001;