rs765486966

Positions:

chrX-47606999-T-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_006950.3(SYN1):c.473A>G(p.Asn158Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000141 in 1,208,670 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 6 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000027 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.000013 ( 0 hom. 6 hem. )

Consequence

SYN1
NM_006950.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.95

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 links:

SYN1 (HGNC:):

SYN1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.20889568).

BS2

High Hemizygotes in GnomAdExome4 at 6 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SYN1	NM_006950.3 linkuse as main transcript	c.473A>G	p.Asn158Ser	missense_variant	3/13	ENST00000295987.13	NP_008881.2	P17600-1
SYN1	NM_133499.2 linkuse as main transcript	c.473A>G	p.Asn158Ser	missense_variant	3/13		NP_598006.1	P17600-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SYN1	ENST00000295987.13 linkuse as main transcript	c.473A>G	p.Asn158Ser	missense_variant	3/13	2	NM_006950.3	ENSP00000295987.7		P17600-1

Frequencies

GnomAD3 genomes

AF:

0.0000271

AC:

AN:

110622

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

32850

show subpopulations

Gnomad AFR

AF:

0.0000659

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:

0.00

Gnomad OTH

AF:

0.000681

GnomAD3 exomes

AF:

0.0000383

AC:

AN:

182875

Hom.:

AF XY:

0.0000445

AC XY:

AN XY:

67399

show subpopulations

Gnomad AFR exome

AF:

0.000152

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000216

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000245

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000127

AC:

AN:

1098048

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

363412

show subpopulations

Gnomad4 AFR exome

AF:

0.0000758

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000662

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000119

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000271

AC:

AN:

110622

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

32850

show subpopulations

Gnomad4 AFR

AF:

0.0000659

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000681

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.0000412

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 27, 2023

This sequence change replaces asparagine, which is neutral and polar, with serine, which is neutral and polar, at codon 158 of the SYN1 protein (p.Asn158Ser). This variant is present in population databases (rs765486966, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with SYN1-related conditions. ClinVar contains an entry for this variant (Variation ID: 465098). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. 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

0.056

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.79

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.37

T;.

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.91

D;D

M_CAP

Benign

0.021

MetaRNN

Benign

0.21

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.9

L;L

PrimateAI

Uncertain

0.52

PROVEAN

Benign

-1.7

N;N

REVEL

Benign

0.13

Sift

Benign

0.037

D;D

Sift4G

Benign

0.10

T;T

Polyphen

0.20

B;P

Vest4

0.41

MutPred

0.48

Gain of sheet (P = 0.039);Gain of sheet (P = 0.039);

MVP

0.52

MPC

0.53

ClinPred

0.088

GERP RS

6.0

Varity_R

0.20

gMVP

0.67

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over