rs397514679

Positions:

• chrX-47574321-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_006950.3(SYN1):​c.1663C>T​(p.Gln555Ter) 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 (★).

• 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

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.215 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• 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 id is 41888.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SYN1	NM_006950.3	c.1663C>T	p.Gln555Ter	stop_gained	12/13	ENST00000295987.13	NP_008881.2
SYN1	NM_133499.2	c.1663C>T	p.Gln555Ter	stop_gained	12/13		NP_598006.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SYN1	ENST00000295987.13	c.1663C>T	p.Gln555Ter	stop_gained	12/13	2	NM_006950.3	ENSP00000295987	P3
SYN1	ENST00000340666.5	c.1663C>T	p.Gln555Ter	stop_gained	12/13	1		ENSP00000343206	A1
SYN1	ENST00000640721.1	c.70+367C>T		intron_variant		5		ENSP00000492857

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

SYN1-related disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 19, 2022

The SYN1 c.1663C>T variant is predicted to result in premature protein termination (p.Gln555*). This variant was reported in an individual with epilepsy (Fassio et al 2011. PubMed ID: 21441247; Lignani G et al 2013. PubMed ID: 23406870; Nguyen DK et al 2015. PubMed ID: 26096837; Cabana JF et al 2018. PubMed ID: 29671924). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Nonsense variants in SYN1 are expected to be pathogenic. This variant is interpreted as pathogenic. -

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 2013

- -

Computational scores

Source: dbNSFP v4.3

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
MutationTaster	Benign	1.0	A;A
Vest4		0.59
GERP RS		4.5

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

Publications

LitVar

Other links and lift over

dbSNP: rs397514679; hg19: chrX-47433720;