chrX-47574760-C-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_006950.3(SYN1):c.1321G>T(p.Ala441Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000878 in 1,184,806 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 27 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A441D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000036 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.000093 ( 0 hom. 27 hem. )

Consequence

SYN1
NM_006950.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:2

Conservation

PhyloP100: 4.23

Publications

0 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: Benign. The variant received -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.068629056).

BP6

Variant X-47574760-C-A is Benign according to our data. Variant chrX-47574760-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 590235.

BS2

High Hemizygotes in GnomAdExome4 at 27 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.1321G>T	p.Ala441Ser	missense	Exon 11 of 13	NP_008881.2	P17600-1
	SYN1	NM_133499.2		c.1321G>T	p.Ala441Ser	missense	Exon 11 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.1321G>T	p.Ala441Ser	missense	Exon 11 of 13	ENSP00000295987.7	P17600-1
SYN1	ENST00000340666.5	TSL:1	c.1321G>T	p.Ala441Ser	missense	Exon 11 of 13	ENSP00000343206.4	P17600-2
SYN1	ENST00000950906.1		c.1318G>T	p.Ala440Ser	missense	Exon 11 of 13	ENSP00000620965.1

Frequencies

GnomAD3 genomes

AF:

0.0000359

AC:

AN:

111337

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:

0.0000757

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000916

AC:

AN:

130933

AF XY:

0.0000235

show subpopulations

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:

0.0000783

Gnomad NFE exome

AF:

0.000209

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000932

AC:

100

AN:

1073469

Hom.:

Cov.:

AF XY:

0.0000772

AC XY:

AN XY:

349619

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26231

American (AMR)

AF:

0.00

AC:

AN:

30252

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18801

East Asian (EAS)

AF:

0.00

AC:

AN:

29430

South Asian (SAS)

AF:

0.00

AC:

AN:

51111

European-Finnish (FIN)

AF:

0.0000259

AC:

AN:

38639

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3862

European-Non Finnish (NFE)

AF:

0.000111

AC:

AN:

829972

Other (OTH)

AF:

0.000155

AC:

AN:

45171

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

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:

0.0000359

AC:

AN:

111337

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33603

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30599

American (AMR)

AF:

0.00

AC:

AN:

10702

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2630

East Asian (EAS)

AF:

0.00

AC:

AN:

3490

South Asian (SAS)

AF:

0.00

AC:

AN:

2644

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6039

Middle Eastern (MID)

AF:

0.00

AC:

AN:

238

European-Non Finnish (NFE)

AF:

0.0000757

AC:

AN:

52821

Other (OTH)

AF:

0.00

AC:

AN:

1498

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.0000868

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.0000266

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

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

History of neurodevelopmental disorder (1)

Inborn genetic diseases (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.81

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.16

FATHMM_MKL

Benign

0.66

LIST_S2

Benign

0.58

M_CAP

Benign

0.014

MetaRNN

Benign

0.069

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

PhyloP100

4.2

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-0.45

REVEL

Benign

0.013

Sift

Benign

0.23

Sift4G

Benign

0.44

Polyphen

0.028

Vest4

0.21

MVP

0.30

MPC

0.63

ClinPred

0.13

GERP RS

4.5

PromoterAI

-0.065

Neutral

(source)

Varity_R

0.14

gMVP

0.14

Mutation Taster

=99/1

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

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