rs1556857481

Variant names:

• chrX-47574544-T-TG
• rs1556857481
• NM_006950.3:c.1439dupC

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_006950.3(SYN1):​c.1439dupC​(p.Leu481IlefsTer203) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely 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 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 2.83
• 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

ACMG classification

Our verdict: Pathogenic. The variant received 18 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-47574544-T-TG is Pathogenic according to our data. Variant chrX-47574544-T-TG is described in ClinVar as [Likely_pathogenic]. Clinvar id is 496675.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYN1	NM_006950.3	c.1439dupC	p.Leu481IlefsTer203	frameshift_variant	Exon 12 of 13	ENST00000295987.13	NP_008881.2
SYN1	NM_133499.2	c.1439dupC	p.Leu481IlefsTer195	frameshift_variant	Exon 12 of 13		NP_598006.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYN1	ENST00000295987.13	c.1439dupC	p.Leu481IlefsTer203	frameshift_variant	Exon 12 of 13	2	NM_006950.3	ENSP00000295987.7
SYN1	ENST00000340666.5	c.1439dupC	p.Leu481IlefsTer195	frameshift_variant	Exon 12 of 13	1		ENSP00000343206.4
SYN1	ENST00000640721.1	c.70+143dupC		intron_variant	Intron 1 of 1	5		ENSP00000492857.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 970603 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 303859

African (AFR) AF: 0.00 AC: 0 AN: 22306

American (AMR) AF: 0.00 AC: 0 AN: 16008

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14053

East Asian (EAS) AF: 0.00 AC: 0 AN: 26758

South Asian (SAS) AF: 0.00 AC: 0 AN: 40001

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 24274

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3501

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 782636

Other (OTH) AF: 0.00 AC: 0 AN: 41066

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Epilepsy, X-linked 1, with variable learning disabilities and behavior disorders Pathogenic:2

Jul 30, 2022

Institute for Human Genetics, University Hospital Essen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 30, 2017

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.8

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: rs1556857481; hg19: chrX-47433943;