rs115212829
Positions:
Variant summary
Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP3BP4_StrongBP6_Very_StrongBS1BS2
The NM_020549.5(CHAT):āc.1135G>Cā(p.Asp379His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000518 in 1,614,242 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (ā ā ).
Frequency
Genomes: š 0.0028 ( 3 hom., cov: 33)
Exomes š: 0.00028 ( 2 hom. )
Consequence
CHAT
NM_020549.5 missense
NM_020549.5 missense
Scores
6
8
4
Clinical Significance
Conservation
PhyloP100: 10.0
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 Benign. Variant got -19 ACMG points.
PP3
Multiple lines of computational evidence support a deleterious effect 6: AlphaMissense, BayesDel_noAF, Cadd, Eigen, phyloP100way_vertebrate, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
BP4
Computational evidence support a benign effect (MetaRNN=0.032766968).
BP6
Variant 10-49646528-G-C is Benign according to our data. Variant chr10-49646528-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 261327.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-49646528-G-C is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00278 (423/152370) while in subpopulation AFR AF= 0.00938 (390/41592). AF 95% confidence interval is 0.00861. There are 3 homozygotes in gnomad4. There are 196 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High Homozygotes in GnomAd4 at 3 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
CHAT | NM_020549.5 | c.1135G>C | p.Asp379His | missense_variant | 8/15 | ENST00000337653.7 | NP_065574.4 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
CHAT | ENST00000337653.7 | c.1135G>C | p.Asp379His | missense_variant | 8/15 | 1 | NM_020549.5 | ENSP00000337103.2 |
Frequencies
GnomAD3 genomes AF: 0.00278 AC: 423AN: 152252Hom.: 3 Cov.: 33
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GnomAD3 exomes AF: 0.000621 AC: 156AN: 251370Hom.: 1 AF XY: 0.000456 AC XY: 62AN XY: 135894
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GnomAD4 exome AF: 0.000283 AC: 413AN: 1461872Hom.: 2 Cov.: 32 AF XY: 0.000246 AC XY: 179AN XY: 727240
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GnomAD4 genome AF: 0.00278 AC: 423AN: 152370Hom.: 3 Cov.: 33 AF XY: 0.00263 AC XY: 196AN XY: 74504
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Benign:2
Benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | - | - - |
Benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Jul 29, 2015 | - - |
Familial infantile myasthenia Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 27, 2024 | - - |
not provided Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Jun 07, 2021 | This variant is associated with the following publications: (PMID: 26582918) - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
.;.;.;D;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
.;.;D;D;D
MetaRNN
Benign
T;T;T;T;T
MetaSVM
Uncertain
D
MutationAssessor
Uncertain
.;.;.;M;.
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D;D;D
REVEL
Pathogenic
Sift
Benign
D;D;D;D;D
Sift4G
Benign
T;T;T;T;T
Polyphen
1.0
.;.;.;D;.
Vest4
MVP
MPC
0.93
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at