rs11551797

Positions:

• chrX-47586541-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BA1

The NM_003254.3(TIMP1):​c.474C>T​(p.Ile158=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0271 in 1,210,261 control chromosomes in the GnomAD database, including 2,074 homozygotes. There are 9,966 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in Lovd as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.033 (236 hom., 1198 hem., cov: 24)
  • Exomes 𝑓: 0.027 (1838 hom. 8768 hem.)
• Consequence: TIMP1 NM_003254.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.158

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.35).
• BP6: Variant X-47586541-C-T is Benign according to our data. Variant chrX-47586541-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.158 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.26 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TIMP1	NM_003254.3	c.474C>T	p.Ile158=	synonymous_variant	6/6	ENST00000218388.9	NP_003245.1
SYN1	NM_006950.3	c.775-9040G>A		intron_variant		ENST00000295987.13	NP_008881.2
SYN1	NM_133499.2	c.775-9040G>A		intron_variant			NP_598006.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TIMP1	ENST00000218388.9	c.474C>T	p.Ile158=	synonymous_variant	6/6	1	NM_003254.3	ENSP00000218388	P1
SYN1	ENST00000295987.13	c.775-9040G>A		intron_variant		2	NM_006950.3	ENSP00000295987	P3

Frequencies

GnomAD3 genomes AF: 0.0326 AC: 3663 AN: 112470 Hom.: 234 Cov.: 24 AF XY: 0.0346 AC XY: 1196 AN XY: 34608

Gnomad AFR AF: 0.00775

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.172

Gnomad ASJ AF: 0.00113

Gnomad EAS AF: 0.276

Gnomad SAS AF: 0.0119

Gnomad FIN AF: 0.000963

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00939

Gnomad OTH AF: 0.0483

GnomAD3 exomes AF: 0.0721 AC: 13103 AN: 181849 Hom.: 1331 AF XY: 0.0558 AC XY: 3717 AN XY: 66641

Gnomad AFR exome AF: 0.00677

Gnomad AMR exome AF: 0.288

Gnomad ASJ exome AF: 0.000940

Gnomad EAS exome AF: 0.297

Gnomad SAS exome AF: 0.00704

Gnomad FIN exome AF: 0.000637

Gnomad NFE exome AF: 0.00840

Gnomad OTH exome AF: 0.0500

GnomAD4 exome AF: 0.0265 AC: 29091 AN: 1097739 Hom.: 1838 Cov.: 31 AF XY: 0.0241 AC XY: 8768 AN XY: 363161

Gnomad4 AFR exome AF: 0.00496

Gnomad4 AMR exome AF: 0.277

Gnomad4 ASJ exome AF: 0.00119

Gnomad4 EAS exome AF: 0.241

Gnomad4 SAS exome AF: 0.00789

Gnomad4 FIN exome AF: 0.00114

Gnomad4 NFE exome AF: 0.0115

Gnomad4 OTH exome AF: 0.0385

GnomAD4 genome AF: 0.0326 AC: 3663 AN: 112522 Hom.: 236 Cov.: 24 AF XY: 0.0346 AC XY: 1198 AN XY: 34670

Gnomad4 AFR AF: 0.00773

Gnomad4 AMR AF: 0.173

Gnomad4 ASJ AF: 0.00113

Gnomad4 EAS AF: 0.275

Gnomad4 SAS AF: 0.0120

Gnomad4 FIN AF: 0.000963

Gnomad4 NFE AF: 0.00939

Gnomad4 OTH AF: 0.0483

Alfa AF: 0.0150 Hom.: 195

Bravo AF: 0.0529

EpiCase AF: 0.00807

EpiControl AF: 0.00872

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.35
CADD	Benign	7.1
DANN	Benign	0.83
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs11551797; hg19: chrX-47445940; COSMIC: COSV54482793; COSMIC: COSV54482793;