X-47574317-C-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_006950.3(SYN1):c.1667G>T(p.Arg556Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 (★★).

Frequency

Genomes: not found (cov: 24)

Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

SYN1
NM_006950.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 2.44

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: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.326644).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYN1	NM_006950.3 link	c.1667G>T	p.Arg556Leu	missense_variant	Exon 12 of 13	ENST00000295987.13	NP_008881.2	P17600-1
SYN1	NM_133499.2 link	c.1667G>T	p.Arg556Leu	missense_variant	Exon 12 of 13		NP_598006.1	P17600-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SYN1	ENST00000295987.13 link	c.1667G>T	p.Arg556Leu	missense_variant	Exon 12 of 13	2	NM_006950.3	ENSP00000295987.7	P17600-1
SYN1	ENST00000340666.5 link	c.1667G>T	p.Arg556Leu	missense_variant	Exon 12 of 13	1		ENSP00000343206.4	P17600-2
SYN1	ENST00000640721.1 link	c.70+371G>T		intron_variant	Intron 1 of 1	5		ENSP00000492857.1	A0A1W2PSE9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

960896

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

301780

African (AFR)

AF:

0.00

AC:

AN:

20226

American (AMR)

AF:

0.00

AC:

AN:

16199

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15736

East Asian (EAS)

AF:

0.00

AC:

AN:

21486

South Asian (SAS)

AF:

0.00

AC:

AN:

38378

European-Finnish (FIN)

AF:

0.00

AC:

AN:

24273

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2589

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

781682

Other (OTH)

AF:

0.00

AC:

AN:

40327

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1

May 16, 2023

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

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

Uncertain:1

Nov 21, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces arginine with leucine at codon 556 of the SYN1 protein (p.Arg556Leu). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and leucine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This variant has not been reported in the literature in individuals with SYN1-related conditions. ClinVar contains an entry for this variant (Variation ID: 569374). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.30

T;.

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.77

T;T

M_CAP

Pathogenic

0.48

MetaRNN

Benign

0.33

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.34

N;N

PhyloP100

2.4

PrimateAI

Pathogenic

0.93

PROVEAN

Benign

-1.6

N;N

REVEL

Benign

0.18

Sift

Uncertain

0.0040

D;D

Sift4G

Benign

0.28

T;T

Polyphen

0.99

D;D

Vest4

0.33

MutPred

0.34

Loss of methylation at R556 (P = 0.111);Loss of methylation at R556 (P = 0.111);

MVP

0.36

MPC

2.4

ClinPred

0.70

GERP RS

4.5

PromoterAI

-0.00010

Neutral

(source)

Varity_R

0.26

gMVP

0.42

Mutation Taster

=83/17

polymorphism

(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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over