rs41298474

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

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. 12/20 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

Publications

1 publications found

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 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: Ambry Genetics, G2P, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Orphanet

SYN1 links:

ENSG00000283743 (HGNC:):

ENSG00000283743 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

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

BP6

Variant X-47575136-G-A is Benign according to our data. Variant chrX-47575136-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 207470.

BS1

Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.000394 (424/1075157) while in subpopulation AMR AF = 0.00201 (64/31850). AF 95% confidence interval is 0.00161. There are 5 homozygotes in GnomAdExome4. There are 125 alleles in the male GnomAdExome4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 14 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYN1	NM_006950.3 link	c.1297C>T	p.His433Tyr	missense_variant	Exon 10 of 13	ENST00000295987.13	NP_008881.2	P17600-1
SYN1	NM_133499.2 link	c.1297C>T	p.His433Tyr	missense_variant	Exon 10 of 13		NP_598006.1	P17600-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SYN1	ENST00000295987.13 link	c.1297C>T	p.His433Tyr	missense_variant	Exon 10 of 13	2	NM_006950.3	ENSP00000295987.7	P17600-1
SYN1	ENST00000340666.5 link	c.1297C>T	p.His433Tyr	missense_variant	Exon 10 of 13	1		ENSP00000343206.4	P17600-2
ENSG00000283743	ENST00000638776.2 link	n.3753C>T		non_coding_transcript_exon_variant	Exon 16 of 16	5

Frequencies

GnomAD3 genomes

AF:

0.000399

AC:

AN:

112773

Hom.:

Cov.:

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

GnomAD2 exomes

AF:

0.00124

AC:

175

AN:

140579

AF XY:

0.000965

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 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

African (AFR)

AF:

0.00

AC:

AN:

25795

American (AMR)

AF:

0.00201

AC:

AN:

31850

Ashkenazi Jewish (ASJ)

AF:

0.0137

AC:

259

AN:

18951

East Asian (EAS)

AF:

0.00

AC:

AN:

28769

South Asian (SAS)

AF:

0.00

AC:

AN:

51232

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38896

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3838

European-Non Finnish (NFE)

AF:

0.0000457

AC:

AN:

830677

Other (OTH)

AF:

0.00140

AC:

AN:

45149

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

106

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000399

AC:

AN:

112828

Hom.:

Cov.:

AF XY:

0.000400

AC XY:

AN XY:

34982

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31132

American (AMR)

AF:

0.000462

AC:

AN:

10813

Ashkenazi Jewish (ASJ)

AF:

0.0117

AC:

AN:

2653

East Asian (EAS)

AF:

0.00

AC:

AN:

3551

South Asian (SAS)

AF:

0.00

AC:

AN:

2775

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6272

Middle Eastern (MID)

AF:

0.00

AC:

AN:

219

European-Non Finnish (NFE)

AF:

0.000113

AC:

AN:

53192

Other (OTH)

AF:

0.00195

AC:

AN:

1538

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.514

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000775

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

Jan 01, 2018

NeuroMeGen, Hospital Clinico Santiago de Compostela

Significance:Likely pathogenic

Review Status:flagged submission

Collection Method:clinical testing

- -

Jan 19, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:1Benign:1

Oct 01, 2018

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 14, 2015

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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). -

SYN1-related disorder

Benign:1

Feb 22, 2022

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

(source)

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

PhyloP100

1.4

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

PromoterAI

0.0012

Neutral

(source)

Varity_R

0.22

gMVP

0.52

Mutation Taster

=96/4

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over