rs1279554995
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Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3PP5
The NM_020549.5(CHAT):c.1840-9A>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000155 in 1,613,806 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000015 ( 0 hom. )
Consequence
CHAT
NM_020549.5 splice_polypyrimidine_tract, intron
NM_020549.5 splice_polypyrimidine_tract, intron
Scores
2
Splicing: ADA: 0.9982
2
Clinical Significance
Conservation
PhyloP100: 0.121
Genes affected
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 Uncertain_significance. Variant got 4 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
Variant 10-49662636-A-G is Pathogenic according to our data. Variant chr10-49662636-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 432145.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=2}.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| CHAT | NM_020549.5 | c.1840-9A>G | splice_polypyrimidine_tract_variant, intron_variant | ENST00000337653.7 | NP_065574.4 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| CHAT | ENST00000337653.7 | c.1840-9A>G | splice_polypyrimidine_tract_variant, intron_variant | 1 | NM_020549.5 | ENSP00000337103 | P2 |
Frequencies
GnomAD3 genomes 0.0000197 AC: 3AN: 152008Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251380Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135868
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GnomAD4 exome AF: 0.0000150 AC: 22AN: 1461798Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 8AN XY: 727200
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GnomAD4 genome 0.0000197 AC: 3AN: 152008Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74250
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 07, 2017 | The c.1840-9 A>G variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Several in silico prediction models predict c.1840-9 A>G may create a new splice acceptor site in intron 13 and lead to abnormal gene splicing. However, in the absence of RNA/functional studies the actual effect of this sequence change is unknown. - |
not specified Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Apr 04, 2024 | Variant summary: CHAT c.1840-9A>G alters a non-conserved nucleotide located at a position not widely known to affect splicing. Several computational tools predict a significant impact on normal splicing: Three predict the variant weakens a 3' canonical acceptor site, and four predict the variant strengthens a 3' cryptic acceptor site. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 4e-06 in 251380 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1840-9A>G has been reported in the literature in at least one compound heterozygous individual affected with Congenital Myasthenic Syndrome (e.g., Dhasakeerthi_2021). However, this data does not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 34431804). ClinVar contains an entry for this variant (Variation ID: 432145). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Familial infantile myasthenia Uncertain:1
| Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jun 27, 2022 | This sequence change falls in intron 13 of the CHAT gene. It does not directly change the encoded amino acid sequence of the CHAT protein. This variant is present in population databases (no rsID available, gnomAD 0.002%). This variant has been observed in individual(s) with clinical features of congenital myasthenic syndrome (Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 432145). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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
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Name
Calibrated prediction
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: 1
DS_AL_spliceai
Position offset: 9
Find out detailed SpliceAI scores and Pangolin per-transcript scores at