rs794727076

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2

The NM_006950.3(SYN1):c.1615G>A(p.Gly539Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000263 in 1,022,489 control chromosomes in the GnomAD database, including 1 homozygotes. There are 78 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/21 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 0.00052 ( 0 hom., 17 hem., cov: 23)

Exomes 𝑓: 0.00023 ( 1 hom. 61 hem. )

Consequence

SYN1
NM_006950.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:4

Conservation

PhyloP100: 1.47

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0074963868).

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000524 (58/110702) while in subpopulation AFR AF = 0.00118 (36/30597). AF 95% confidence interval is 0.000874. There are 0 homozygotes in GnomAd4. There are 17 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Hemizygotes in GnomAd4 at 17 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYN1	NM_006950.3 link	c.1615G>A	p.Gly539Ser	missense_variant	Exon 12 of 13	ENST00000295987.13	NP_008881.2	P17600-1
SYN1	NM_133499.2 link	c.1615G>A	p.Gly539Ser	missense_variant	Exon 12 of 13		NP_598006.1	P17600-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SYN1	ENST00000295987.13 link	c.1615G>A	p.Gly539Ser	missense_variant	Exon 12 of 13	2	NM_006950.3	ENSP00000295987.7	P17600-1
SYN1	ENST00000340666.5 link	c.1615G>A	p.Gly539Ser	missense_variant	Exon 12 of 13	1		ENSP00000343206.4	P17600-2
SYN1	ENST00000640721.1 link	c.70+319G>A		intron_variant	Intron 1 of 1	5		ENSP00000492857.1	A0A1W2PSE9

Frequencies

GnomAD3 genomes

AF:

0.000524

AC:

AN:

110675

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00118

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000280

Gnomad ASJ

AF:

0.00344

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00448

Gnomad NFE

AF:

0.000153

Gnomad OTH

AF:

0.000667

GnomAD2 exomes

AF:

0.000522

AC:

AN:

3831

AF XY:

0.00346

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00995

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000231

AC:

211

AN:

911787

Hom.:

Cov.:

AF XY:

0.000214

AC XY:

AN XY:

284817

show subpopulations

African (AFR)

AF:

0.000746

AC:

AN:

18771

American (AMR)

AF:

0.00

AC:

AN:

8683

Ashkenazi Jewish (ASJ)

AF:

0.00467

AC:

AN:

12424

East Asian (EAS)

AF:

0.00

AC:

AN:

21259

South Asian (SAS)

AF:

0.00

AC:

AN:

30323

European-Finnish (FIN)

AF:

0.00

AC:

AN:

22068

Middle Eastern (MID)

AF:

0.000833

AC:

AN:

2400

European-Non Finnish (NFE)

AF:

0.000148

AC:

112

AN:

757703

Other (OTH)

AF:

0.000655

AC:

AN:

38156

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

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:

0.000524

AC:

AN:

110702

Hom.:

Cov.:

AF XY:

0.000509

AC XY:

AN XY:

33412

show subpopulations

African (AFR)

AF:

0.00118

AC:

AN:

30597

American (AMR)

AF:

0.000280

AC:

AN:

10732

Ashkenazi Jewish (ASJ)

AF:

0.00344

AC:

AN:

2620

East Asian (EAS)

AF:

0.00

AC:

AN:

3419

South Asian (SAS)

AF:

0.00

AC:

AN:

2679

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6050

Middle Eastern (MID)

AF:

0.00503

AC:

AN:

199

European-Non Finnish (NFE)

AF:

0.000153

AC:

AN:

52228

Other (OTH)

AF:

0.000660

AC:

AN:

1515

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.542

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:

0.000487

Hom.:

Bravo

AF:

0.000601

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3Benign:2

Feb 27, 2015

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The G539S 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 in approximately 1,400 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The G539S 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. However, this substitution alters a position that is poorly conserved across species, and in silico analysis predicts G539S likely does not alter the protein structure/function. The variant is found in EPILEPSY panel(s). -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Dec 22, 2017

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 12, 2020

Athena Diagnostics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Inborn genetic diseases

Uncertain:1

May 19, 2020

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1615G>A (p.G539S) alteration is located in exon 12 (coding exon 12) of the SYN1 gene. This alteration results from a G to A substitution at nucleotide position 1615, causing the glycine (G) at amino acid position 539 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

SYN1-related disorder

Benign:1

Aug 03, 2023

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). -

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

Benign:1

Jan 22, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.66

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.15

T;.

FATHMM_MKL

Benign

0.42

LIST_S2

Benign

0.76

T;T

M_CAP

Uncertain

0.22

MetaRNN

Benign

0.0075

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.34

N;N

PhyloP100

1.5

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

-0.40

N;N

REVEL

Benign

0.050

Sift

Uncertain

0.021

D;D

Sift4G

Benign

0.67

T;T

Polyphen

0.14

B;B

Vest4

0.30

MutPred

0.34

Gain of phosphorylation at G539 (P = 0.0062);Gain of phosphorylation at G539 (P = 0.0062);

MVP

0.38

MPC

2.9

ClinPred

0.069

GERP RS

3.4

PromoterAI

-0.071

Neutral

(source)

Varity_R

0.14

gMVP

0.24

Mutation Taster

=90/10

polymorphism

(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