rs748323076

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_006950.3(SYN1):c.1369G>C(p.Ala457Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000253 in 1,184,396 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 9 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A457D) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., 5 hem., cov: 23)

Exomes 𝑓: 0.000011 ( 0 hom. 4 hem. )

Consequence

SYN1
NM_006950.3 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 2.66

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: 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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.042538762).

BP6

Variant X-47574712-C-G is Benign according to our data. Variant chrX-47574712-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 465089.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Hemizygotes in GnomAd4 at 5 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYN1	NM_006950.3	MANE Select	c.1369G>C	p.Ala457Pro	missense	Exon 11 of 13	NP_008881.2
	SYN1	NM_133499.2		c.1369G>C	p.Ala457Pro	missense	Exon 11 of 13	NP_598006.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
SYN1	ENST00000295987.13	TSL:2 MANE Select	c.1369G>C	p.Ala457Pro	missense	Exon 11 of 13	ENSP00000295987.7
SYN1	ENST00000340666.5	TSL:1	c.1369G>C	p.Ala457Pro	missense	Exon 11 of 13	ENSP00000343206.4
SYN1	ENST00000640721.1	TSL:5	c.46G>C	p.Ala16Pro	missense	Exon 1 of 2	ENSP00000492857.1

Frequencies

GnomAD3 genomes

AF:

0.000161

AC:

AN:

111563

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000554

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000932

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000234

AC:

AN:

128058

AF XY:

0.0000241

show subpopulations

Gnomad AFR exome

AF:

0.000383

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:

0.0000112

AC:

AN:

1072833

Hom.:

Cov.:

AF XY:

0.0000114

AC XY:

AN XY:

349941

show subpopulations

African (AFR)

AF:

0.000381

AC:

AN:

26235

American (AMR)

AF:

0.00

AC:

AN:

29949

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18786

East Asian (EAS)

AF:

0.00

AC:

AN:

29317

South Asian (SAS)

AF:

0.00

AC:

AN:

51059

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38509

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3873

European-Non Finnish (NFE)

AF:

0.00000241

AC:

AN:

829963

Other (OTH)

AF:

0.00

AC:

AN:

45142

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

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:

0.000161

AC:

AN:

111563

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

33875

show subpopulations

African (AFR)

AF:

0.000554

AC:

AN:

30671

American (AMR)

AF:

0.0000932

AC:

AN:

10735

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2640

East Asian (EAS)

AF:

0.00

AC:

AN:

3494

South Asian (SAS)

AF:

0.00

AC:

AN:

2658

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6102

Middle Eastern (MID)

AF:

0.00

AC:

AN:

238

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

52862

Other (OTH)

AF:

0.00

AC:

AN:

1489

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

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:

0.0000712

Hom.:

Bravo

AF:

0.000212

ExAC

AF:

0.0000535

AC:

ClinVar

ClinVar submissions as Germline

Significance:Likely benign

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 (1)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.52

CADD

Uncertain

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.20

FATHMM_MKL

Benign

0.73

LIST_S2

Benign

0.71

M_CAP

Benign

0.030

MetaRNN

Benign

0.043

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.55

PhyloP100

2.7

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-1.1

REVEL

Benign

0.17

Sift

Benign

0.19

Sift4G

Benign

0.49

Polyphen

0.98

Vest4

0.35

MVP

0.44

MPC

0.87

ClinPred

0.074

GERP RS

4.3

PromoterAI

-0.012

Neutral

(source)

Varity_R

0.39

gMVP

0.27

Mutation Taster

=96/4

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over