rs150248483

Positions:

• chrX-47576182-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_006950.3(SYN1):​c.1107C>T​(p.Ile369=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00167 in 1,203,169 control chromosomes in the GnomAD database, including 1 homozygotes. There are 629 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., 32 hem., cov: 23)
  • Exomes 𝑓: 0.0017 (1 hom. 597 hem.)
• Consequence: SYN1 NM_006950.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:5
• Conservation: PhyloP100: 0.988

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant X-47576182-G-A is Benign according to our data. Variant chrX-47576182-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 96363.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=3, Benign=2}. Variant chrX-47576182-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.988 with no splicing effect.
• BS2: High Hemizygotes in GnomAd4 at 32 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYN1	NM_006950.3	c.1107C>T	p.Ile369=	synonymous_variant	9/13	ENST00000295987.13
SYN1	NM_133499.2	c.1107C>T	p.Ile369=	synonymous_variant	9/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYN1	ENST00000295987.13	c.1107C>T	p.Ile369=	synonymous_variant	9/13	2	NM_006950.3	P3
SYN1	ENST00000340666.5	c.1107C>T	p.Ile369=	synonymous_variant	9/13	1		A1

Frequencies

GnomAD3 genomes AF: 0.00102 AC: 114 AN: 111993 Hom.: 0 Cov.: 23 AF XY: 0.000937 AC XY: 32 AN XY: 34165

Gnomad AFR AF: 0.000260

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000471

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000165

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00188

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00100 AC: 166 AN: 165485 Hom.: 0 AF XY: 0.000958 AC XY: 51 AN XY: 53223

Gnomad AFR exome AF: 0.000169

Gnomad AMR exome AF: 0.000231

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: 0.00216

Gnomad OTH exome AF: 0.000474

GnomAD4 exome AF: 0.00174 AC: 1894 AN: 1091124 Hom.: 1 Cov.: 32 AF XY: 0.00167 AC XY: 597 AN XY: 357802

Gnomad4 AFR exome AF: 0.000305

Gnomad4 AMR exome AF: 0.000145

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000250

Gnomad4 NFE exome AF: 0.00220

Gnomad4 OTH exome AF: 0.000742

GnomAD4 genome AF: 0.00102 AC: 114 AN: 112045 Hom.: 0 Cov.: 23 AF XY: 0.000935 AC XY: 32 AN XY: 34227

Gnomad4 AFR AF: 0.000259

Gnomad4 AMR AF: 0.000470

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000165

Gnomad4 NFE AF: 0.00188

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00105 Hom.: 7

Bravo AF: 0.00104

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:2

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 22, 2015	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2019	- -

not specified Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 03, 2013	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	May 11, 2015	- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 23, 2016

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 21, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	4.3
DANN	Benign	0.63

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: rs150248483; hg19: chrX-47435581;