X-47585009-G-C

Variant names:

• chrX-47585009-G-C
• rs61756234
• NM_003254.3:c.195G>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_003254.3(TIMP1):​c.195G>C​(p.Met65Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 1 hem.)
  • Failed GnomAD Quality Control
• Consequence: TIMP1 NM_003254.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.271

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29707366).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TIMP1	NM_003254.3	c.195G>C	p.Met65Ile	missense_variant	Exon 3 of 6	ENST00000218388.9	NP_003245.1
SYN1	NM_006950.3	c.775-7508C>G		intron_variant	Intron 5 of 12	ENST00000295987.13	NP_008881.2
SYN1	NM_133499.2	c.775-7508C>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.195G>C	p.Met65Ile	missense_variant	Exon 3 of 6	1	NM_003254.3	ENSP00000218388.4
SYN1	ENST00000295987.13	c.775-7508C>G		intron_variant	Intron 5 of 12	2	NM_006950.3	ENSP00000295987.7

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 9.12e-7 AC: 1 AN: 1097055 Hom.: 0 Cov.: 31 AF XY: 0.00000276 AC XY: 1 AN XY: 362453

Gnomad4 AFR exome AF: 0.0000379

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

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

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Benign	-0.0048	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	17
DANN	Benign	0.97
DEOGEN2	Uncertain	0.63	D;T;.;T
FATHMM_MKL	Benign	0.63	D
LIST_S2	Benign	0.75	T;D;D;D
M_CAP	Benign	0.065	D
MetaRNN	Benign	0.23	T;T;T;T
MetaSVM	Benign	-0.56	T
MutationAssessor	Uncertain	2.1	M;.;.;.
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-2.3	N;N;N;N
REVEL	Benign	0.23
Sift	Benign	0.28	T;T;D;T
Sift4G	Benign	0.50	T;T;T;T
Polyphen		0.018	B;.;.;.
Vest4		0.18
MutPred		0.59		Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);.;.;
MVP		0.83
MPC		0.32
ClinPred		0.11	T
GERP RS		1.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.21
gMVP		0.68

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

Publications

LitVar

Other links and lift over

dbSNP: rs61756234; hg19: chrX-47444408;