rs1057517665
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_003055.3(SLC18A3):āc.557G>Cā(p.Gly186Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,456,228 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ).
Frequency
Genomes: not found (cov: 35)
Exomes š: 6.9e-7 ( 0 hom. )
Consequence
SLC18A3
NM_003055.3 missense
NM_003055.3 missense
Scores
15
3
1
Clinical Significance
Conservation
PhyloP100: 9.67
Genes affected
SLC18A3 (HGNC:10936): (solute carrier family 18 member A3) This gene is a member of the vesicular amine transporter family. The encoded transmembrane protein transports acetylcholine into secretory vesicles for release into the extracellular space. Acetylcholine transport utilizes a proton gradient established by a vacuolar ATPase. This gene is located within the first intron of the choline acetyltransferase gene. [provided by RefSeq, Jul 2008]
CHAT (HGNC:1912): (choline O-acetyltransferase) This gene encodes an enzyme which catalyzes the biosynthesis of the neurotransmitter acetylcholine. This gene product is a characteristic feature of cholinergic neurons, and changes in these neurons may explain some of the symptoms of Alzheimer's disease. Polymorphisms in this gene have been associated with Alzheimer's disease and mild cognitive impairment. Mutations in this gene are associated with congenital myasthenic syndrome associated with episodic apnea. Multiple transcript variants encoding different isoforms have been found for this gene, and some of these variants have been shown to encode more than one isoform. [provided by RefSeq, May 2010]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.986
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
SLC18A3 | NM_003055.3 | c.557G>C | p.Gly186Ala | missense_variant | 1/1 | ENST00000374115.5 | |
CHAT | NM_020984.4 | c.-69+2098G>C | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
SLC18A3 | ENST00000374115.5 | c.557G>C | p.Gly186Ala | missense_variant | 1/1 | NM_003055.3 | P1 | ||
CHAT | ENST00000339797.5 | c.-69+2098G>C | intron_variant | 1 | A2 |
Frequencies
GnomAD3 genomes ? Cov.: 35
GnomAD3 genomes
?
Cov.:
35
GnomAD4 exome AF: 6.87e-7 AC: 1AN: 1456228Hom.: 0 Cov.: 80 AF XY: 0.00000138 AC XY: 1AN XY: 724770
GnomAD4 exome
AF:
AC:
1
AN:
1456228
Hom.:
Cov.:
80
AF XY:
AC XY:
1
AN XY:
724770
Gnomad4 AFR exome
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GnomAD4 genome ? Cov.: 35
GnomAD4 genome
?
Cov.:
35
ClinVar
Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Congenital myasthenic syndrome 21 Pathogenic:1Uncertain:1
Uncertain significance, criteria provided, single submitter | research | Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard | May 27, 2020 | The heterozygous p.Gly186Ala variant in SLC18A3 was identified by our study, in the compound heterozygous state, along with a pathogenic deletion, in an individual with autosomal recessive congenital myasthenic syndrome (PMID: 27590285). It is of note that the deletion spans across at least 5 genes including SLC18A3. The p.Gly186Ala variant has been reported pathogenic by OMIM in ClinVar (Variation ID: 372159) and was absent from large population studies. Computational prediction tools and conservation analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine impact. Furthermore, although this gene has been reported in association with congenital myasthenic syndrome, it currently has moderate evidence for these associations. In summary, the clinical significance of the p.Gly186Ala variant is uncertain. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Dec 06, 2016 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
H
MutationTaster
Benign
D;D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift
Pathogenic
D
Sift4G
Pathogenic
D
Polyphen
D
Vest4
MutPred
Loss of methylation at R182 (P = 0.1644);
MVP
ClinPred
D
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