rs191822319

chrX-47576226-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_006950.3(SYN1):c.1063C>T(p.Leu355=) 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

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 Benign. Variant got -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 id is 465085.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Hemizygotes in GnomAd at 8 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYN1	NM_006950.3	c.1063C>T	p.Leu355=	synonymous_variant	9/13	ENST00000295987.13
SYN1	NM_133499.2	c.1063C>T	p.Leu355=	synonymous_variant	9/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYN1	ENST00000295987.13	c.1063C>T	p.Leu355=	synonymous_variant	9/13	2	NM_006950.3	P3
SYN1	ENST00000340666.5	c.1063C>T	p.Leu355=	synonymous_variant	9/13	1		A1

Frequencies

GnomAD3 genomes AF: 0.000259 AC: 29 AN: 112167 Hom.: 0 Cov.: 23 AF XY: 0.000233 AC XY: 8 AN XY: 34343

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

GnomAD3 exomes AF: 0.000213 AC: 34 AN: 159937 Hom.: 0 AF XY: 0.000161 AC XY: 8 AN XY: 49759

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 SAS 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

Gnomad4 AFR exome AF: 0.000535

Gnomad4 AMR exome AF: 0.000502

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000571

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000741

Gnomad4 OTH exome AF: 0.000109

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

Gnomad4 AFR AF: 0.000422

Gnomad4 AMR AF: 0.000375

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000225

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000648 Hom.: 4

Bravo AF: 0.000276

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Nov 28, 2017

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 01, 2017

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 16, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
Cadd	Benign	9.4
Dann	Benign	0.66

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

Publications

LitVar

Other links and lift over

dbSNP: rs191822319; hg19: chrX-47435625;