NM_003254.3:c.388A>T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_003254.3(TIMP1):​c.388A>T​(p.Ser130Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000897 in 111,541 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S130R) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000090 (0 hom., 1 hem., cov: 23)
• Consequence: TIMP1 NM_003254.3 missense
• Clinical Significance: Not reported in ClinVar
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TIMP1	NM_003254.3	c.388A>T	p.Ser130Cys	missense_variant	Exon 5 of 6	ENST00000218388.9	NP_003245.1
SYN1	NM_006950.3	c.775-8101T>A		intron_variant	Intron 5 of 12	ENST00000295987.13	NP_008881.2
SYN1	NM_133499.2	c.775-8101T>A		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>T	p.Ser130Cys	missense_variant	Exon 5 of 6	1	NM_003254.3	ENSP00000218388.4
SYN1	ENST00000295987.13	c.775-8101T>A		intron_variant	Intron 5 of 12	2	NM_006950.3	ENSP00000295987.7

Frequencies

GnomAD3 genomes AF: 0.00000897 AC: 1 AN: 111541 Hom.: 0 Cov.: 23 AF XY: 0.0000297 AC XY: 1 AN XY: 33709

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000189

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 34

GnomAD4 genome AF: 0.00000897 AC: 1 AN: 111541 Hom.: 0 Cov.: 23 AF XY: 0.0000297 AC XY: 1 AN XY: 33709

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000189

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Uncertain	0.71	D;.
FATHMM_MKL	Benign	0.42	N
LIST_S2	Benign	0.63	T;T
M_CAP	Uncertain	0.26	D
MetaRNN	Uncertain	0.43	T;T
MetaSVM	Uncertain	0.48	D
MutationAssessor	Uncertain	2.8	M;.
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-3.4	D;D
REVEL	Uncertain	0.58
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.025	D;D
Polyphen		1.0	D;.
Vest4		0.36
MVP		0.85
MPC		0.89
ClinPred		0.96	D
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.44
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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;