X-47574336-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_006950.3(SYN1):c.1648G>A(p.Ala550Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000249 in 1,042,104 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A550F) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000045 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.000023 ( 0 hom. 2 hem. )

Consequence

SYN1
NM_006950.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts P:1U:3

Conservation

PhyloP100: 1.19

Publications

13 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: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.16033694).

BS2

High Hemizygotes in GnomAdExome4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYN1	NM_006950.3 link	c.1648G>A	p.Ala550Thr	missense_variant	Exon 12 of 13	ENST00000295987.13	NP_008881.2
SYN1	NM_133499.2 link	c.1648G>A	p.Ala550Thr	missense_variant	Exon 12 of 13		NP_598006.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
SYN1	ENST00000295987.13 link	c.1648G>A	p.Ala550Thr	missense_variant	Exon 12 of 13	2	NM_006950.3	ENSP00000295987.7
SYN1	ENST00000340666.5 link	c.1648G>A	p.Ala550Thr	missense_variant	Exon 12 of 13	1		ENSP00000343206.4
SYN1	ENST00000640721.1 link	c.70+352G>A		intron_variant	Intron 1 of 1	5		ENSP00000492857.1

Frequencies

GnomAD3 genomes

AF:

0.0000455

AC:

AN:

109930

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000962

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00

AC:

AN:

17090

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

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:

0.0000225

AC:

AN:

932174

Hom.:

Cov.:

AF XY:

0.00000689

AC XY:

AN XY:

290248

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

19569

American (AMR)

AF:

0.00

AC:

AN:

12457

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

13907

East Asian (EAS)

AF:

0.00

AC:

AN:

21213

South Asian (SAS)

AF:

0.00

AC:

AN:

33569

European-Finnish (FIN)

AF:

0.00

AC:

AN:

23086

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2491

European-Non Finnish (NFE)

AF:

0.0000261

AC:

AN:

766812

Other (OTH)

AF:

0.0000256

AC:

AN:

39070

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.517

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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:

0.0000455

AC:

AN:

109930

Hom.:

Cov.:

AF XY:

0.0000303

AC XY:

AN XY:

32954

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

30318

American (AMR)

AF:

0.00

AC:

AN:

10658

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2610

East Asian (EAS)

AF:

0.00

AC:

AN:

3393

South Asian (SAS)

AF:

0.00

AC:

AN:

2693

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5954

Middle Eastern (MID)

AF:

0.00

AC:

AN:

216

European-Non Finnish (NFE)

AF:

0.0000962

AC:

AN:

51951

Other (OTH)

AF:

0.00

AC:

AN:

1484

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0139372), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.388

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:

0.00

Hom.:

Bravo

AF:

0.0000302

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

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

Pathogenic:1Uncertain:1

Jun 15, 2011

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Aug 28, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 550 of the SYN1 protein (p.Ala550Thr). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the gnomAD database. This missense change has been observed in individuals with SYN1-related conditions (PMID: 21441247; internal data). This variant is also known as p.Ala548Thr. ClinVar contains an entry for this variant (Variation ID: 41889). Algorithms developed to predict the effect of variants on gene product structure and function are not available or were not evaluated for this variant. Experimental studies have shown that this missense change affects SYN1 function (PMID: 21441247, 26173895). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified

Uncertain:1

Aug 15, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: SYN1 c.1648G>A (p.Ala550Thr) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 17090 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1648G>A has been reported in the literature in individuals affected with epilepsy, autism spectrum disorder, and schizophrenia (examples: Fassio_2011, and Mojarad_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Epilepsy, X-linked 1, with variable learning disabilities and behavior disorders. Experimental studies have reported the variant affects normal protein function however is insufficient to determine the role of this variant in disease (examples: Fassio_2011, and Tang_2014). The following publications have been ascertained in the context of this evaluation (PMID: 21441247, 33526774, 26173895). One submitter has cited clinical-significance assessments for this variant to ClinVar after 2014 and has classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

SYN1-related disorder

Uncertain:1

Feb 08, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The SYN1 c.1648G>A variant is predicted to result in the amino acid substitution p.Ala550Thr. This variant has been reported to be causative for autism spectrum disorders with or without epilepsy in four unrelated French Canadian patients (Fassio et al. 2011 et al. PubMed ID: 21441247). Functional studies showed that this variant displayed impaired targeting to nerve terminals (Fassio et al. 2011 et al. PubMed ID: 21441247; Tang et al. 2015. PubMed ID: 26173895, reported as A548T). This variant has not been reported in a large population database, indicating this variant is rare. However, it has conflicting interpretations regarding its pathogenicity in ClinVar, ranging from pathogenic to uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/41889/). Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.20

T;.

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.64

T;T

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.16

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

N;N

PhyloP100

1.2

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

-0.64

N;N

REVEL

Benign

0.15

Sift

Benign

0.28

T;T

Sift4G

Benign

0.54

T;T

Polyphen

0.43

B;P

Vest4

0.71

MutPred

0.32

Gain of phosphorylation at A550 (P = 0.0062);Gain of phosphorylation at A550 (P = 0.0062);

MVP

0.75

MPC

2.4

ClinPred

0.57

GERP RS

4.5

PromoterAI

-0.077

Neutral

(source)

Varity_R

0.082

gMVP

0.29

Mutation Taster

=41/59

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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