rs397514679

Variant names:

• chrX-47574321-G-A
• rs397514679
• NM_006950.3:c.1663C>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_006950.3(SYN1):​c.1663C>T​(p.Gln555*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 24)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: SYN1 NM_006950.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 3.72
• Publications: 24 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: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, Laboratory for Molecular Medicine, G2P
• intellectual disability, X-linked 50

  Inheritance: XL Classification: STRONG Submitted by: PanelApp Australia

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-47574321-G-A is Pathogenic according to our data. Variant chrX-47574321-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 41888.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYN1	NM_006950.3	MANE Select	c.1663C>T	p.Gln555*	stop_gained	Exon 12 of 13	NP_008881.2	P17600-1
	SYN1	NM_133499.2		c.1663C>T	p.Gln555*	stop_gained	Exon 12 of 13	NP_598006.1	P17600-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYN1	ENST00000295987.13	TSL:2 MANE Select	c.1663C>T	p.Gln555*	stop_gained	Exon 12 of 13	ENSP00000295987.7	P17600-1
	SYN1	ENST00000340666.5	TSL:1	c.1663C>T	p.Gln555*	stop_gained	Exon 12 of 13	ENSP00000343206.4	P17600-2
	SYN1	ENST00000950906.1		c.1660C>T	p.Gln554*	stop_gained	Exon 12 of 13	ENSP00000620965.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 958156 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 300692

African (AFR) AF: 0.00 AC: 0 AN: 20104

American (AMR) AF: 0.00 AC: 0 AN: 15397

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15548

East Asian (EAS) AF: 0.00 AC: 0 AN: 21476

South Asian (SAS) AF: 0.00 AC: 0 AN: 37992

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 24190

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2586

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 780683

Other (OTH) AF: 0.00 AC: 0 AN: 40180

GnomAD4 genome Cov.: 24

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Epilepsy, X-linked 1, with variable learning disabilities and behavior disorders (1)
1	-	-	SYN1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	37
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.82	D
PhyloP100		3.7
Vest4		0.59
GERP RS		4.5
PromoterAI		-0.021	Neutral
Mutation Taster		=13/187	disease causing (ClinVar)

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: rs397514679; hg19: chrX-47433720;