X-47585586-T-C

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_003254.3(TIMP1):c.372T>C(p.Phe124=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.461 in 1,194,351 control chromosomes in the GnomAD database, including 85,727 homozygotes. There are 178,638 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.46 (8491 hom., 14986 hem., cov: 22)
  • Exomes 𝑓: 0.46 (77236 hom. 163652 hem.)
• Consequence: TIMP1 NM_003254.3 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.721

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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant X-47585586-T-C is Benign according to our data. Variant chrX-47585586-T-C is described in ClinVar as [Benign]. Clinvar id is 1165693.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-47585586-T-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.721 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.493 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TIMP1	NM_003254.3	c.372T>C	p.Phe124=	synonymous_variant	5/6	ENST00000218388.9
SYN1	NM_006950.3	c.775-8085A>G		intron_variant		ENST00000295987.13
SYN1	NM_133499.2	c.775-8085A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TIMP1	ENST00000218388.9	c.372T>C	p.Phe124=	synonymous_variant	5/6	1	NM_003254.3	P1
SYN1	ENST00000295987.13	c.775-8085A>G		intron_variant		2	NM_006950.3	P3

Frequencies

GnomAD3 genomes AF: 0.463 AC: 51051 AN: 110273 Hom.: 8482 Cov.: 22 AF XY: 0.459 AC XY: 14948 AN XY: 32549

Gnomad AFR AF: 0.472

Gnomad AMI AF: 0.400

Gnomad AMR AF: 0.438

Gnomad ASJ AF: 0.441

Gnomad EAS AF: 0.438

Gnomad SAS AF: 0.517

Gnomad FIN AF: 0.468

Gnomad MID AF: 0.366

Gnomad NFE AF: 0.464

Gnomad OTH AF: 0.466

GnomAD3 exomes AF: 0.463 AC: 74441 AN: 160949 Hom.: 11891 AF XY: 0.469 AC XY: 22946 AN XY: 48961

Gnomad AFR exome AF: 0.473

Gnomad AMR exome AF: 0.423

Gnomad ASJ exome AF: 0.428

Gnomad EAS exome AF: 0.444

Gnomad SAS exome AF: 0.525

Gnomad FIN exome AF: 0.484

Gnomad NFE exome AF: 0.466

Gnomad OTH exome AF: 0.435

GnomAD4 exome AF: 0.460 AC: 499057 AN: 1084023 Hom.: 77236 Cov.: 36 AF XY: 0.464 AC XY: 163652 AN XY: 352501

Gnomad4 AFR exome AF: 0.476

Gnomad4 AMR exome AF: 0.429

Gnomad4 ASJ exome AF: 0.430

Gnomad4 EAS exome AF: 0.460

Gnomad4 SAS exome AF: 0.524

Gnomad4 FIN exome AF: 0.484

Gnomad4 NFE exome AF: 0.457

Gnomad4 OTH exome AF: 0.455

GnomAD4 genome AF: 0.463 AC: 51098 AN: 110328 Hom.: 8491 Cov.: 22 AF XY: 0.459 AC XY: 14986 AN XY: 32614

Gnomad4 AFR AF: 0.472

Gnomad4 AMR AF: 0.438

Gnomad4 ASJ AF: 0.441

Gnomad4 EAS AF: 0.439

Gnomad4 SAS AF: 0.516

Gnomad4 FIN AF: 0.468

Gnomad4 NFE AF: 0.464

Gnomad4 OTH AF: 0.471

Alfa AF: 0.460 Hom.: 22817

Bravo AF: 0.464

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Epilepsy, X-linked 1, with variable learning disabilities and behavior disorders Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	7.2
Dann	Benign	0.59
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs4898; hg19: chrX-47444985; COSMIC: COSV54483037; COSMIC: COSV54483037;