rs191822319

Variant names:

• chrX-47576226-G-A
• rs191822319
• NM_006950.3:c.1063C>T

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_006950.3(SYN1):​c.1063C>T​(p.Leu355Leu) variant causes a synonymous change. The variant allele was found at a frequency of 0.000112 in 1,199,988 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 35 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L355L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., 8 hem., cov: 23)
  • Exomes 𝑓: 0.000097 (0 hom. 27 hem.)
• Consequence: SYN1 NM_006950.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.98
• Publications: 1 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

ENSG00000283743 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant X-47576226-G-A is Benign according to our data. Variant chrX-47576226-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 465085.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Hemizygotes in GnomAd4 at 8 XL gene

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.1063C>T	p.Leu355Leu	synonymous	Exon 9 of 13	NP_008881.2	P17600-1
	SYN1	NM_133499.2		c.1063C>T	p.Leu355Leu	synonymous	Exon 9 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.1063C>T	p.Leu355Leu	synonymous	Exon 9 of 13	ENSP00000295987.7	P17600-1
	SYN1	ENST00000340666.5	TSL:1	c.1063C>T	p.Leu355Leu	synonymous	Exon 9 of 13	ENSP00000343206.4	P17600-2
	SYN1	ENST00000950906.1		c.1060C>T	p.Leu354Leu	synonymous	Exon 9 of 13	ENSP00000620965.1

Frequencies

GnomAD3 genomes AF: 0.000259 AC: 29 AN: 112167 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.000423

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000376

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: 0.000225

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000213 AC: 34 AN: 159937 AF XY: 0.000161

Gnomad AFR exome AF: 0.000442

Gnomad AMR exome AF: 0.000633

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000159

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.0000965 AC: 105 AN: 1087773 Hom.: 0 Cov.: 32 AF XY: 0.0000760 AC XY: 27 AN XY: 355249

African (AFR) AF: 0.000535 AC: 14 AN: 26151

American (AMR) AF: 0.000502 AC: 17 AN: 33871

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19213

East Asian (EAS) AF: 0.00 AC: 0 AN: 29716

South Asian (SAS) AF: 0.0000571 AC: 3 AN: 52584

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39774

Middle Eastern (MID) AF: 0.000970 AC: 4 AN: 4125

European-Non Finnish (NFE) AF: 0.0000741 AC: 62 AN: 836600

Other (OTH) AF: 0.000109 AC: 5 AN: 45739

GnomAD4 genome AF: 0.000258 AC: 29 AN: 112215 Hom.: 0 Cov.: 23 AF XY: 0.000233 AC XY: 8 AN XY: 34401

African (AFR) AF: 0.000422 AC: 13 AN: 30794

American (AMR) AF: 0.000375 AC: 4 AN: 10661

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2657

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 2751

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6137

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.000225 AC: 12 AN: 53217

Other (OTH) AF: 0.00 AC: 0 AN: 1533

Alfa AF: 0.000648 Hom.: 4

Bravo AF: 0.000276

ClinVar

ClinVar submissions

Significance: Likely benign

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	Inborn genetic diseases (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	9.4
DANN	Benign	0.66
PhyloP100		4.0
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs191822319; hg19: chrX-47435625;