rs145911562

chrX-47607150-T-C

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_006950.3(SYN1):c.426A>G(p.Lys142=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00113 in 1,209,945 control chromosomes in the GnomAD database, including 6 homozygotes. There are 597 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00067 (0 hom., 23 hem., cov: 22)
  • Exomes 𝑓: 0.0012 (6 hom. 574 hem.)
• Consequence: SYN1 NM_006950.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.52

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant X-47607150-T-C is Benign according to our data. Variant chrX-47607150-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 207459.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-47607150-T-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=2.52 with no splicing effect.
• BS2: High Hemizygotes in GnomAd at 24 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYN1	NM_006950.3	c.426A>G	p.Lys142=	synonymous_variant	2/13	ENST00000295987.13
SYN1	NM_133499.2	c.426A>G	p.Lys142=	synonymous_variant	2/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYN1	ENST00000295987.13	c.426A>G	p.Lys142=	synonymous_variant	2/13	2	NM_006950.3	P3
SYN1	ENST00000340666.5	c.426A>G	p.Lys142=	synonymous_variant	2/13	1		A1
SYN1	ENST00000639776.1	c.87A>G	p.Lys29=	synonymous_variant	2/6	3

Frequencies

GnomAD3 genomes AF: 0.000678 AC: 76 AN: 112028 Hom.: 0 Cov.: 22 AF XY: 0.000702 AC XY: 24 AN XY: 34198

Gnomad AFR AF: 0.0000325

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000190

Gnomad ASJ AF: 0.00113

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00554

Gnomad FIN AF: 0.000985

Gnomad MID AF: 0.00418

Gnomad NFE AF: 0.000883

Gnomad OTH AF: 0.000668

GnomAD3 exomes AF: 0.00122 AC: 224 AN: 183391 Hom.: 2 AF XY: 0.00189 AC XY: 128 AN XY: 67853

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000729

Gnomad ASJ exome AF: 0.000267

Gnomad EAS exome AF: 0.000144

Gnomad SAS exome AF: 0.00792

Gnomad FIN exome AF: 0.000812

Gnomad NFE exome AF: 0.000586

Gnomad OTH exome AF: 0.00132

GnomAD4 exome AF: 0.00117 AC: 1288 AN: 1097866 Hom.: 6 Cov.: 30 AF XY: 0.00158 AC XY: 574 AN XY: 363232

Gnomad4 AFR exome AF: 0.000152

Gnomad4 AMR exome AF: 0.000142

Gnomad4 ASJ exome AF: 0.000361

Gnomad4 EAS exome AF: 0.0000662

Gnomad4 SAS exome AF: 0.00939

Gnomad4 FIN exome AF: 0.000592

Gnomad4 NFE exome AF: 0.000766

Gnomad4 OTH exome AF: 0.00158

GnomAD4 genome AF: 0.000669 AC: 75 AN: 112079 Hom.: 0 Cov.: 22 AF XY: 0.000671 AC XY: 23 AN XY: 34259

Gnomad4 AFR AF: 0.0000324

Gnomad4 AMR AF: 0.000189

Gnomad4 ASJ AF: 0.00113

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00556

Gnomad4 FIN AF: 0.000985

Gnomad4 NFE AF: 0.000883

Gnomad4 OTH AF: 0.000659

Alfa AF: 0.000618 Hom.: 4

Bravo AF: 0.000434

EpiCase AF: 0.000872

EpiControl AF: 0.000771

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 05, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 20, 2015	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 27, 2024

- -

History of neurodevelopmental disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 31, 2016

Synonymous alterations with insufficient evidence to classify as benign -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
Cadd	Benign	14
Dann	Benign	0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs145911562; hg19: chrX-47466549;