rs772106134

Positions:

Variant summary

Our verdict is Benign. Variant got -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. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

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

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 590235.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3}.

BS2

High Hemizygotes in GnomAdExome4 at 27 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SYN1	NM_006950.3 linkuse as main transcript	c.1321G>T	p.Ala441Ser	missense_variant	11/13	ENST00000295987.13	NP_008881.2	P17600-1
SYN1	NM_133499.2 linkuse as main transcript	c.1321G>T	p.Ala441Ser	missense_variant	11/13		NP_598006.1	P17600-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SYN1	ENST00000295987.13 linkuse as main transcript	c.1321G>T	p.Ala441Ser	missense_variant	11/13	2	NM_006950.3	ENSP00000295987.7	P17600-1
SYN1	ENST00000340666.5 linkuse as main transcript	c.1321G>T	p.Ala441Ser	missense_variant	11/13	1		ENSP00000343206.4	P17600-2
SYN1	ENST00000640721.1 linkuse as main transcript	c.-3G>T		upstream_gene_variant		5		ENSP00000492857.1	A0A1W2PSE9

Frequencies

GnomAD3 genomes

AF:

0.0000359

AC:

AN:

111337

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33603

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

GnomAD3 exomes

AF:

0.0000916

AC:

AN:

130933

Hom.:

AF XY:

0.0000235

AC XY:

AN XY:

42639

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 SAS 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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000259

Gnomad4 NFE exome

AF:

0.000111

Gnomad4 OTH exome

AF:

0.000155

GnomAD4 genome

AF:

0.0000359

AC:

AN:

111337

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33603

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000757

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000868

Hom.:

Bravo

AF:

0.0000416

ExAC

AF:

0.0000266

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

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

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 06, 2023	This sequence change replaces alanine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 441 of the SYN1 protein (p.Ala441Ser). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 590235). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 10, 2019	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Jun 24, 2022

BP4 -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 17, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

History of neurodevelopmental disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 12, 2013

In silico models in agreement (benign);Other data supporting benign classification -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.81

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.16

T;.

FATHMM_MKL

Benign

0.66

LIST_S2

Benign

0.58

T;T

M_CAP

Benign

0.014

MetaRNN

Benign

0.069

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

N;N

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-0.45

N;N

REVEL

Benign

0.013

Sift

Benign

0.23

T;T

Sift4G

Benign

0.44

T;T

Polyphen

0.028

B;B

Vest4

0.21

MVP

0.30

MPC

0.63

ClinPred

0.13

GERP RS

4.5

Varity_R

0.14

gMVP

0.14

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