NM_006950.3:c.1699A>G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_006950.3(SYN1):​c.1699A>G​(p.Thr567Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00247 in 1,101,774 control chromosomes in the GnomAD database, including 48 homozygotes. There are 755 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.013 ( 24 hom., 427 hem., cov: 24)
Exomes 𝑓: 0.0012 ( 24 hom. 328 hem. )

Consequence

SYN1
NM_006950.3 missense

Scores

1
15

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:13

Conservation

PhyloP100: -0.218
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.00393793).
BP6
Variant X-47574285-T-C is Benign according to our data. Variant chrX-47574285-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 41890.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=8, Likely_benign=1}. Variant chrX-47574285-T-C is described in Lovd as [Likely_benign]. Variant chrX-47574285-T-C is described in Lovd as [Benign].
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0135 (1506/111841) while in subpopulation AFR AF= 0.0468 (1442/30814). AF 95% confidence interval is 0.0448. There are 24 homozygotes in gnomad4. There are 427 alleles in male gnomad4 subpopulation. Median coverage is 24. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 24 XL gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SYN1NM_006950.3 linkc.1699A>G p.Thr567Ala missense_variant Exon 12 of 13 ENST00000295987.13 NP_008881.2 P17600-1
SYN1NM_133499.2 linkc.1699A>G p.Thr567Ala missense_variant Exon 12 of 13 NP_598006.1 P17600-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
SYN1ENST00000295987.13 linkc.1699A>G p.Thr567Ala missense_variant Exon 12 of 13 2 NM_006950.3 ENSP00000295987.7 P17600-1
SYN1ENST00000340666.5 linkc.1699A>G p.Thr567Ala missense_variant Exon 12 of 13 1 ENSP00000343206.4 P17600-2
SYN1ENST00000640721.1 linkc.70+403A>G intron_variant Intron 1 of 1 5 ENSP00000492857.1 A0A1W2PSE9

Frequencies

GnomAD3 genomes
AF:
0.0135
AC:
1505
AN:
111798
Hom.:
24
Cov.:
24
AF XY:
0.0125
AC XY:
427
AN XY:
34240
show subpopulations
Gnomad AFR
AF:
0.0468
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00343
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.0129
Gnomad NFE
AF:
0.000303
Gnomad OTH
AF:
0.00597
GnomAD3 exomes
AF:
0.00113
AC:
61
AN:
53883
Hom.:
1
AF XY:
0.000326
AC XY:
6
AN XY:
18429
show subpopulations
Gnomad AFR exome
AF:
0.0459
Gnomad AMR exome
AF:
0.00201
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000152
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00122
AC:
1212
AN:
989933
Hom.:
24
Cov.:
32
AF XY:
0.00103
AC XY:
328
AN XY:
318907
show subpopulations
Gnomad4 AFR exome
AF:
0.0474
Gnomad4 AMR exome
AF:
0.00229
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000454
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000566
Gnomad4 OTH exome
AF:
0.00266
GnomAD4 genome
AF:
0.0135
AC:
1506
AN:
111841
Hom.:
24
Cov.:
24
AF XY:
0.0125
AC XY:
427
AN XY:
34295
show subpopulations
Gnomad4 AFR
AF:
0.0468
Gnomad4 AMR
AF:
0.00333
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000303
Gnomad4 OTH
AF:
0.00589
Alfa
AF:
0.00626
Hom.:
41
Bravo
AF:
0.0151
ExAC
AF:
0.00137
AC:
68

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:13
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Benign:6
Apr 16, 2018
Athena Diagnostics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Sep 17, 2024
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Genome Diagnostics Laboratory, University Medical Center Utrecht
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Aug 22, 2017
Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Nov 01, 2024
CeGaT Center for Human Genetics Tuebingen
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

SYN1: BS1, BS2 -

not specified Uncertain:1Benign:3
Jun 05, 2015
Genetic Services Laboratory, University of Chicago
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Jan 22, 2015
Eurofins Ntd Llc (ga)
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Dec 15, 2016
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Epilepsy, X-linked 1, with variable learning disabilities and behavior disorders Benign:2
Nov 21, 2018
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 03, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Intellectual disability, X-linked 50 Uncertain:1
Jun 15, 2011
OMIM
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: literature only

- -

SYN1-related disorder Benign:1
Jun 18, 2021
PreventionGenetics, part of Exact Sciences
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

History of neurodevelopmental disorder Benign:1
Jun 22, 2017
Ambry Genetics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

General population or sub-population frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance;General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance;In silico models in agreement (benign);Subpopulation frequency in support of benign classification -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.066
BayesDel_addAF
Benign
-0.55
T
BayesDel_noAF
Benign
-0.52
CADD
Benign
11
DANN
Benign
0.67
DEOGEN2
Benign
0.15
T;.
FATHMM_MKL
Benign
0.56
D
LIST_S2
Benign
0.51
T;T
MetaRNN
Benign
0.0039
T;T
MetaSVM
Benign
-0.96
T
MutationAssessor
Benign
0.0
N;N
PrimateAI
Pathogenic
0.86
D
PROVEAN
Benign
-0.15
N;N
REVEL
Benign
0.27
Sift
Benign
0.43
T;T
Sift4G
Benign
0.90
T;T
Polyphen
0.0
B;B
Vest4
0.66
MVP
0.92
MPC
2.0
ClinPred
0.0060
T
GERP RS
0.73
Varity_R
0.039
gMVP
0.21

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.

Other links and lift over

dbSNP: rs200533370; hg19: chrX-47433684; COSMIC: COSV55983533; COSMIC: COSV55983533; API