rs185229386

Variant names:

• chrX-47575250-T-C
• rs185229386
• NM_006950.3:c.1183A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006950.3(SYN1):​c.1183A>G​(p.Ile395Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000177 in 112,771 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I395T) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.000018 (0 hom., 0 hem., cov: 23)
• Consequence: SYN1 NM_006950.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 2.47
• Publications: 0 publications found

Genes affected

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: Ambry Genetics, G2P, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Orphanet

ENSG00000283743 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14625537).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006950.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYN1	NM_006950.3	MANE Select	c.1183A>G	p.Ile395Val	missense	Exon 10 of 13	NP_008881.2
	SYN1	NM_133499.2		c.1183A>G	p.Ile395Val	missense	Exon 10 of 13	NP_598006.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYN1	ENST00000295987.13	TSL:2 MANE Select	c.1183A>G	p.Ile395Val	missense	Exon 10 of 13	ENSP00000295987.7
	SYN1	ENST00000340666.5	TSL:1	c.1183A>G	p.Ile395Val	missense	Exon 10 of 13	ENSP00000343206.4
	ENSG00000283743	ENST00000638776.2	TSL:5	n.3639A>G		non_coding_transcript_exon	Exon 16 of 16

Frequencies

GnomAD3 genomes AF: 0.0000177 AC: 2 AN: 112718 Hom.: 0 Cov.: 23

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: 0.0000376

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome AF: 0.0000177 AC: 2 AN: 112771 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34927

African (AFR) AF: 0.00 AC: 0 AN: 31100

American (AMR) AF: 0.00 AC: 0 AN: 10780

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2646

East Asian (EAS) AF: 0.00 AC: 0 AN: 3564

South Asian (SAS) AF: 0.00 AC: 0 AN: 2774

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6261

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 217

European-Non Finnish (NFE) AF: 0.0000376 AC: 2 AN: 53218

Other (OTH) AF: 0.00 AC: 0 AN: 1523

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Epilepsy, X-linked 1, with variable learning disabilities and behavior disorders (1)
-	1	-	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.31	T
FATHMM_MKL	Benign	0.66	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		2.5
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-0.74	N
REVEL	Benign	0.052
Sift	Benign	0.072	T
Sift4G	Benign	0.10	T
Polyphen		0.17	B
Vest4		0.26
MVP		0.46
MPC		0.71
ClinPred		0.66	D
GERP RS		4.0
PromoterAI		-0.055	Neutral
Varity_R		0.12
gMVP		0.83
Mutation Taster		=93/7	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: rs185229386; hg19: chrX-47434649;