rs187134574

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_006950.3(SYN1):c.152C>G(p.Ala51Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00227 in 1,165,532 control chromosomes in the GnomAD database, including 42 homozygotes. There are 670 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 Benign (★★).

Frequency

Genomes: 𝑓 0.012 ( 26 hom., 356 hem., cov: 22)

Exomes 𝑓: 0.0012 ( 16 hom. 314 hem. )

Consequence

SYN1
NM_006950.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 2.64

Publications

10 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0026123822).

BP6

Variant X-47619577-G-C is Benign according to our data. Variant chrX-47619577-G-C is described in ClinVar as Benign. ClinVar VariationId is 139384.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0122 (1361/111764) while in subpopulation AFR AF = 0.0423 (1302/30808). AF 95% confidence interval is 0.0404. There are 26 homozygotes in GnomAd4. There are 356 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 26 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYN1	NM_006950.3 link	c.152C>G	p.Ala51Gly	missense_variant	Exon 1 of 13	ENST00000295987.13	NP_008881.2	P17600-1
SYN1	NM_133499.2 link	c.152C>G	p.Ala51Gly	missense_variant	Exon 1 of 13		NP_598006.1	P17600-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SYN1	ENST00000295987.13 link	c.152C>G	p.Ala51Gly	missense_variant	Exon 1 of 13	2	NM_006950.3	ENSP00000295987.7	P17600-1
SYN1	ENST00000340666.5 link	c.152C>G	p.Ala51Gly	missense_variant	Exon 1 of 13	1		ENSP00000343206.4	P17600-2
ENSG00000283743	ENST00000638776.2 link	n.2833+3513C>G		intron_variant	Intron 7 of 15	5
SYN1	ENST00000639776.1 link	c.-191C>G		upstream_gene_variant		3		ENSP00000492521.1	A0A1W2PS00

Frequencies

GnomAD3 genomes

AF:

0.0122

AC:

1359

AN:

111715

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0423

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00297

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000745

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0128

Gnomad NFE

AF:

0.000265

Gnomad OTH

AF:

0.00469

GnomAD2 exomes

AF:

0.00260

AC:

274

AN:

105205

AF XY:

0.00120

show subpopulations

Gnomad AFR exome

AF:

0.0512

Gnomad AMR exome

AF:

0.00132

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000764

Gnomad OTH exome

AF:

0.000677

GnomAD4 exome

AF:

0.00121

AC:

1280

AN:

1053768

Hom.:

Cov.:

AF XY:

0.000927

AC XY:

314

AN XY:

338668

show subpopulations

African (AFR)

AF:

0.0450

AC:

1104

AN:

24512

American (AMR)

AF:

0.00161

AC:

AN:

29140

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18483

East Asian (EAS)

AF:

0.00

AC:

AN:

27751

South Asian (SAS)

AF:

0.00

AC:

AN:

50184

European-Finnish (FIN)

AF:

0.00

AC:

AN:

36074

Middle Eastern (MID)

AF:

0.000564

AC:

AN:

3547

European-Non Finnish (NFE)

AF:

0.0000403

AC:

AN:

819852

Other (OTH)

AF:

0.00213

AC:

AN:

44225

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

116

175

233

291

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

102

136

170

<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:

0.0122

AC:

1361

AN:

111764

Hom.:

Cov.:

AF XY:

0.0105

AC XY:

356

AN XY:

34010

show subpopulations

African (AFR)

AF:

0.0423

AC:

1302

AN:

30808

American (AMR)

AF:

0.00297

AC:

AN:

10769

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2637

East Asian (EAS)

AF:

0.00

AC:

AN:

3515

South Asian (SAS)

AF:

0.00112

AC:

AN:

2676

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6205

Middle Eastern (MID)

AF:

0.0140

AC:

AN:

214

European-Non Finnish (NFE)

AF:

0.000265

AC:

AN:

52755

Other (OTH)

AF:

0.00464

AC:

AN:

1510

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

104

155

207

259

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00705

Hom.:

Bravo

AF:

0.0138

ESP6500AA

AF:

0.0176

AC:

ESP6500EA

AF:

0.000219

AC:

ExAC

AF:

0.00250

AC:

250

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Jun 15, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 09, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 23871722, 21441247, 27884173) -

Apr 16, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Jul 19, 2016

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

History of neurodevelopmental disorder

Benign:1

Jan 08, 2016

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance;In silico models in agreement (benign);In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Subpopulation frequency in support of benign classification -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.76

BayesDel_noAF

Benign

-0.83

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.22

T;.

FATHMM_MKL

Benign

0.46

LIST_S2

Benign

0.63

T;T

MetaRNN

Benign

0.0026

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.55

N;N

PhyloP100

2.6

PrimateAI

Uncertain

0.79

PROVEAN

Benign

-0.61

N;N

REVEL

Benign

0.051

Sift

Benign

0.28

T;T

Sift4G

Benign

0.34

T;T

Polyphen

0.0010

B;B

Vest4

0.66

MVP

0.34

MPC

0.80

ClinPred

0.0041

GERP RS

3.1

PromoterAI

-0.0020

Neutral

(source)

Varity_R

0.096

gMVP

0.35

Mutation Taster

=99/1

polymorphism (auto)

(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