20-10275498-G-A
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 3P and 6B. PM1PP2BP4_ModerateBS2
The NM_130811.4(SNAP25):c.7G>A(p.Glu3Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000355 in 1,603,676 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000037 ( 1 hom. )
Consequence
SNAP25
NM_130811.4 missense
NM_130811.4 missense
Scores
2
5
12
Clinical Significance
Conservation
PhyloP100: 9.20
Genes affected
SNAP25 (HGNC:11132): (synaptosome associated protein 25) Synaptic vesicle membrane docking and fusion is mediated by SNAREs (soluble N-ethylmaleimide-sensitive factor attachment protein receptors) located on the vesicle membrane (v-SNAREs) and the target membrane (t-SNAREs). The assembled v-SNARE/t-SNARE complex consists of a bundle of four helices, one of which is supplied by v-SNARE and the other three by t-SNARE. For t-SNAREs on the plasma membrane, the protein syntaxin supplies one helix and the protein encoded by this gene contributes the other two. Therefore, this gene product is a presynaptic plasma membrane protein involved in the regulation of neurotransmitter release. Two alternative transcript variants encoding different protein isoforms have been described for this gene. [provided by RefSeq, Jul 2008]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -3 ACMG points.
PM1
?
In a region_of_interest Interaction with CENPF (size 74) in uniprot entity SNP25_HUMAN there are 11 pathogenic changes around while only 4 benign (73%) in NM_130811.4
PP2
?
Missense variant where missense usually causes diseases, SNAP25
BP4
?
Computational evidence support a benign effect (MetaRNN=0.083487004).
BS2
?
High AC in GnomAdExome at 14 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SNAP25 | NM_130811.4 | c.7G>A | p.Glu3Lys | missense_variant | 2/8 | ENST00000254976.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SNAP25 | ENST00000254976.7 | c.7G>A | p.Glu3Lys | missense_variant | 2/8 | 1 | NM_130811.4 | P5 | |
SNAP25-AS1 | ENST00000421143.6 | n.6-78561C>T | intron_variant, non_coding_transcript_variant | 5 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152190Hom.: 0 Cov.: 33
GnomAD3 genomes
?
AF:
AC:
3
AN:
152190
Hom.:
Cov.:
33
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD3 exomes AF: 0.0000591 AC: 14AN: 236866Hom.: 0 AF XY: 0.0000706 AC XY: 9AN XY: 127558
GnomAD3 exomes
AF:
AC:
14
AN:
236866
Hom.:
AF XY:
AC XY:
9
AN XY:
127558
Gnomad AFR exome
AF:
Gnomad AMR exome
AF:
Gnomad ASJ exome
AF:
Gnomad EAS exome
AF:
Gnomad SAS exome
AF:
Gnomad FIN exome
AF:
Gnomad NFE exome
AF:
Gnomad OTH exome
AF:
GnomAD4 exome AF: 0.0000372 AC: 54AN: 1451368Hom.: 1 Cov.: 30 AF XY: 0.0000347 AC XY: 25AN XY: 720998
GnomAD4 exome
AF:
AC:
54
AN:
1451368
Hom.:
Cov.:
30
AF XY:
AC XY:
25
AN XY:
720998
Gnomad4 AFR exome
AF:
Gnomad4 AMR exome
AF:
Gnomad4 ASJ exome
AF:
Gnomad4 EAS exome
AF:
Gnomad4 SAS exome
AF:
Gnomad4 FIN exome
AF:
Gnomad4 NFE exome
AF:
Gnomad4 OTH exome
AF:
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152308Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74464
GnomAD4 genome
?
AF:
AC:
3
AN:
152308
Hom.:
Cov.:
33
AF XY:
AC XY:
2
AN XY:
74464
Gnomad4 AFR
AF:
Gnomad4 AMR
AF:
Gnomad4 ASJ
AF:
Gnomad4 EAS
AF:
Gnomad4 SAS
AF:
Gnomad4 FIN
AF:
Gnomad4 NFE
AF:
Gnomad4 OTH
AF:
Alfa
AF:
Hom.:
Bravo
AF:
ExAC
?
AF:
AC:
12
Asia WGS
AF:
AC:
1
AN:
3478
ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Congenital myasthenic syndrome 18 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 13, 2023 | This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 3 of the SNAP25 protein (p.Glu3Lys). 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 SNAP25-related conditions. ClinVar contains an entry for this variant (Variation ID: 1441827). 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Benign
Cadd
Uncertain
Dann
Uncertain
DEOGEN2
Benign
T;.;.
Eigen
Benign
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D
M_CAP
Benign
T
MetaRNN
Benign
T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
N;N;.
MutationTaster
Benign
D;D
PrimateAI
Pathogenic
D
PROVEAN
Benign
N;N;N
REVEL
Benign
Sift
Benign
T;T;T
Sift4G
Benign
T;T;T
Polyphen
B;B;.
Vest4
MutPred
Gain of ubiquitination at E3 (P = 0.0066);Gain of ubiquitination at E3 (P = 0.0066);Gain of ubiquitination at E3 (P = 0.0066);
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at