rs397514680

Variant names:

Your query was ambiguous. Multiple possible variants found:

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: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics, Laboratory for Molecular Medicine, G2P
intellectual disability, X-linked 50
Inheritance: XL Classification: STRONG Submitted by: PanelApp Australia

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006950.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYN1	NM_006950.3	MANE Select	c.1648G>A	p.Ala550Thr	missense	Exon 12 of 13	NP_008881.2	P17600-1
	SYN1	NM_133499.2		c.1648G>A	p.Ala550Thr	missense	Exon 12 of 13	NP_598006.1	P17600-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SYN1	ENST00000295987.13	TSL:2 MANE Select	c.1648G>A	p.Ala550Thr	missense	Exon 12 of 13	ENSP00000295987.7	P17600-1
SYN1	ENST00000340666.5	TSL:1	c.1648G>A	p.Ala550Thr	missense	Exon 12 of 13	ENSP00000343206.4	P17600-2
SYN1	ENST00000950906.1		c.1645G>A	p.Ala549Thr	missense	Exon 12 of 13	ENSP00000620965.1

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

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Epilepsy, X-linked 1, with variable learning disabilities and behavior disorders (2)

not specified (1)

SYN1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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

FATHMM_MKL

Uncertain

0.82

LIST_S2

Benign

0.64

M_CAP

Uncertain

0.17

MetaRNN

Benign

0.16

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PhyloP100

1.2

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

-0.64

REVEL

Benign

0.15

Sift

Benign

0.28

Sift4G

Benign

0.54

Polyphen

0.43

Vest4

0.71

MutPred

0.32

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over