rs41298474

Positions:

chrX-47575136-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_006950.3(SYN1):c.1297C>T(p.His433Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000395 in 1,187,985 control chromosomes in the GnomAD database, including 5 homozygotes. There are 139 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00040 ( 0 hom., 14 hem., cov: 24)

Exomes 𝑓: 0.00039 ( 5 hom. 125 hem. )

Consequence

SYN1
NM_006950.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1B:3

Conservation

PhyloP100: 1.35

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0062771738).

BS2

High Hemizygotes in GnomAd4 at 14 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SYN1	NM_006950.3 linkuse as main transcript	c.1297C>T	p.His433Tyr	missense_variant	10/13	ENST00000295987.13	NP_008881.2
SYN1	NM_133499.2 linkuse as main transcript	c.1297C>T	p.His433Tyr	missense_variant	10/13		NP_598006.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SYN1	ENST00000295987.13 linkuse as main transcript	c.1297C>T	p.His433Tyr	missense_variant	10/13	2	NM_006950.3	ENSP00000295987	P3	P17600-1
SYN1	ENST00000340666.5 linkuse as main transcript	c.1297C>T	p.His433Tyr	missense_variant	10/13	1		ENSP00000343206	A1	P17600-2

Frequencies

GnomAD3 genomes

AF:

0.000399

AC:

AN:

112773

Hom.:

Cov.:

AF XY:

0.000401

AC XY:

AN XY:

34917

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000463

Gnomad ASJ

AF:

0.0117

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000113

Gnomad OTH

AF:

0.00197

GnomAD3 exomes

AF:

0.00124

AC:

175

AN:

140579

Hom.:

AF XY:

0.000965

AC XY:

AN XY:

43525

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00211

Gnomad ASJ exome

AF:

0.0141

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000240

Gnomad OTH exome

AF:

0.00455

GnomAD4 exome

AF:

0.000394

AC:

424

AN:

1075157

Hom.:

Cov.:

AF XY:

0.000357

AC XY:

125

AN XY:

350147

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00201

Gnomad4 ASJ exome

AF:

0.0137

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000457

Gnomad4 OTH exome

AF:

0.00140

GnomAD4 genome

AF:

0.000399

AC:

AN:

112828

Hom.:

Cov.:

AF XY:

0.000400

AC XY:

AN XY:

34982

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000462

Gnomad4 ASJ

AF:

0.0117

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000113

Gnomad4 OTH

AF:

0.00195

Alfa

AF:

0.000796

Hom.:

Bravo

AF:

0.000620

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000894

AC:

ExAC

AF:

0.000852

AC:

101

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

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

Pathogenic:1Benign:1

Likely pathogenic, criteria provided, single submitter	clinical testing	NeuroMeGen, Hospital Clinico Santiago de Compostela	Jan 01, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

not provided

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jan 14, 2015	p.His433Tyr (CAT>TAT): c.1297 C>T in exon 10 of the SYN1 gene (NM_133499.2) A variant of unknown significance has been identified in the SYN1 gene. The H433Y missense change has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project. The H433Y variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved across species. However, multiple in silico algorithms predict it is non-pathogenic. Therefore, based on the currently available information, it is unclear whether H433Y is a disease-causing mutation or a rare benign variant. The variant is found in CHILD-EPI, EPILEPSY panel(s). -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2018	- -

SYN1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 22, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.58

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.29

T;.

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.74

T;T

MetaRNN

Benign

0.0063

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

N;N

MutationTaster

Benign

0.58

N;N

PrimateAI

Uncertain

0.74

PROVEAN

Benign

-1.1

N;N

REVEL

Benign

0.062

Sift

Benign

0.46

T;T

Sift4G

Benign

0.88

T;T

Polyphen

0.96

D;P

Vest4

0.23

MVP

0.26

MPC

1.2

ClinPred

0.067

GERP RS

5.0

Varity_R

0.22

gMVP

0.52

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over