X-47574020-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_006950.3(SYN1):​c.1964C>T​(p.Pro655Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000967 in 1,034,585 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 24)
Exomes 𝑓: 9.7e-7 ( 0 hom. 0 hem. )

Consequence

SYN1
NM_006950.3 missense

Scores

4
13

Clinical Significance

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

Conservation

PhyloP100: 1.46
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 Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.1451951).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
SYN1NM_006950.3 linkc.1964C>T p.Pro655Leu missense_variant Exon 12 of 13 ENST00000295987.13 NP_008881.2 P17600-1
SYN1NM_133499.2 linkc.1964C>T p.Pro655Leu 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.1964C>T p.Pro655Leu missense_variant Exon 12 of 13 2 NM_006950.3 ENSP00000295987.7 P17600-1
SYN1ENST00000340666.5 linkc.1964C>T p.Pro655Leu missense_variant Exon 12 of 13 1 ENSP00000343206.4 P17600-2
SYN1ENST00000640721.1 linkc.70+668C>T intron_variant Intron 1 of 1 5 ENSP00000492857.1 A0A1W2PSE9

Frequencies

GnomAD3 genomes
Cov.:
24
GnomAD4 exome
AF:
9.67e-7
AC:
1
AN:
1034585
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
332719
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:
0.0000350
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
24
Alfa
AF:
0.000132
Hom.:
1
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Uncertain:1
Apr 07, 2017
Eurofins Ntd Llc (ga)
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Epilepsy, X-linked 1, with variable learning disabilities and behavior disorders Uncertain:1
Jul 30, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 655 of the SYN1 protein (p.Pro655Leu). This variant is not present in population databases (gnomAD no frequency). 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: 501096). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Not Available". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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
0.086
BayesDel_addAF
Benign
-0.27
T
BayesDel_noAF
Benign
-0.63
CADD
Uncertain
25
DANN
Uncertain
0.99
DEOGEN2
Benign
0.30
T;.
FATHMM_MKL
Benign
0.28
N
LIST_S2
Benign
0.65
T;D
M_CAP
Benign
0.043
D
MetaRNN
Benign
0.15
T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.8
L;L
PrimateAI
Uncertain
0.71
T
PROVEAN
Benign
-1.8
N;N
REVEL
Benign
0.033
Sift
Uncertain
0.0030
D;D
Sift4G
Uncertain
0.014
D;D
Polyphen
0.0010
B;B
Vest4
0.17
MutPred
0.29
Loss of glycosylation at P655 (P = 0.0185);Loss of glycosylation at P655 (P = 0.0185);
MVP
0.28
MPC
1.8
ClinPred
0.74
D
GERP RS
2.3
Varity_R
0.13
gMVP
0.24

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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: rs1333198986; hg19: chrX-47433419; API