rs61756234

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chrX-47585009-G-A
• chrX-47585009-G-C
• chrX-47585009-G-T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_003254.3(TIMP1):​c.195G>A​(p.Met65Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000384 in 1,208,306 control chromosomes in the GnomAD database, including 2 homozygotes. There are 133 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00024 (1 hom., 6 hem., cov: 23)
  • Exomes 𝑓: 0.00040 (1 hom. 127 hem.)
• Consequence: TIMP1 NM_003254.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.271
• Publications: 0 publications found

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]

SYN1 Gene-Disease associations (from GenCC):

• X-linked complex neurodevelopmental disorder

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• epilepsy, X-linked 1, with variable learning disabilities and behavior disorders

  Inheritance: XL Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Orphanet, G2P, Ambry Genetics, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)

ENSG00000283743 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.16863927).
• BS2: High Hemizygotes in GnomAd4 at 6 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003254.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TIMP1	NM_003254.3	MANE Select	c.195G>A	p.Met65Ile	missense	Exon 3 of 6	NP_003245.1	P01033
	SYN1	NM_006950.3	MANE Select	c.775-7508C>T		intron	N/A	NP_008881.2	P17600-1
	SYN1	NM_133499.2		c.775-7508C>T		intron	N/A	NP_598006.1	P17600-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TIMP1	ENST00000218388.9	TSL:1 MANE Select	c.195G>A	p.Met65Ile	missense	Exon 3 of 6	ENSP00000218388.4	P01033
	TIMP1	ENST00000456754.6	TSL:1	c.195G>A	p.Met65Ile	missense	Exon 3 of 4	ENSP00000406671.2	Q5H9B5
	SYN1	ENST00000295987.13	TSL:2 MANE Select	c.775-7508C>T		intron	N/A	ENSP00000295987.7	P17600-1

Frequencies

GnomAD3 genomes AF: 0.000243 AC: 27 AN: 111251 Hom.: 1 Cov.: 23

Gnomad AFR AF: 0.0000982

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: 0.000434

Gnomad OTH AF: 0.000661

GnomAD2 exomes AF: 0.000227 AC: 41 AN: 180814 AF XY: 0.000260

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000252

Gnomad NFE exome AF: 0.000422

Gnomad OTH exome AF: 0.000673

GnomAD4 exome AF: 0.000398 AC: 437 AN: 1097055 Hom.: 1 Cov.: 31 AF XY: 0.000350 AC XY: 127 AN XY: 362453

African (AFR) AF: 0.0000758 AC: 2 AN: 26388

American (AMR) AF: 0.00 AC: 0 AN: 35143

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19313

East Asian (EAS) AF: 0.00 AC: 0 AN: 30198

South Asian (SAS) AF: 0.00 AC: 0 AN: 53903

European-Finnish (FIN) AF: 0.000519 AC: 21 AN: 40479

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4134

European-Non Finnish (NFE) AF: 0.000475 AC: 400 AN: 841442

Other (OTH) AF: 0.000304 AC: 14 AN: 46055

GnomAD4 genome AF: 0.000243 AC: 27 AN: 111251 Hom.: 1 Cov.: 23 AF XY: 0.000179 AC XY: 6 AN XY: 33427

African (AFR) AF: 0.0000982 AC: 3 AN: 30549

American (AMR) AF: 0.00 AC: 0 AN: 10456

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2634

East Asian (EAS) AF: 0.00 AC: 0 AN: 3565

South Asian (SAS) AF: 0.00 AC: 0 AN: 2632

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5934

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 238

European-Non Finnish (NFE) AF: 0.000434 AC: 23 AN: 53047

Other (OTH) AF: 0.000661 AC: 1 AN: 1513

Alfa AF: 0.000145 Hom.: 3

Bravo AF: 0.000215

ExAC AF: 0.000231 AC: 28

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Uncertain	0.63	D
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.066	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.56	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		0.27
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.23
Sift	Benign	0.28	T
Sift4G	Benign	0.50	T
Polyphen		0.018	B
Vest4		0.18
MutPred		0.59		Gain of sheet (P = 0.0827)
MVP		0.83
MPC		0.32
ClinPred		0.033	T
GERP RS		1.1
PromoterAI		-0.049	Neutral
Varity_R		0.21
gMVP		0.68
Mutation Taster		=163/37	polymorphism

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

Other links and lift over

dbSNP: rs61756234; hg19: chrX-47444408;