rs1554801418

Variant names:

• chr10-49614409-A-G
• rs1554801418
• NM_020549.5:c.220A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020549.5(CHAT):​c.220A>G​(p.Thr74Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000717 in 1,394,742 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T74I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: CHAT NM_020549.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.354
• Publications: 0 publications found

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]

CHAT Gene-Disease associations (from GenCC):

• congenital myasthenic syndrome 6

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• presynaptic congenital myasthenic syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07113221).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHAT	NM_020549.5	c.220A>G	p.Thr74Ala	missense_variant	Exon 1 of 15	ENST00000337653.7	NP_065574.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHAT	ENST00000337653.7	c.220A>G	p.Thr74Ala	missense_variant	Exon 1 of 15	1	NM_020549.5	ENSP00000337103.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.17e-7 AC: 1 AN: 1394742 Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0 AN XY: 687792

African (AFR) AF: 0.00 AC: 0 AN: 31514

American (AMR) AF: 0.00 AC: 0 AN: 35656

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25142

East Asian (EAS) AF: 0.00 AC: 0 AN: 35718

South Asian (SAS) AF: 0.00 AC: 0 AN: 79114

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47474

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4064

European-Non Finnish (NFE) AF: 9.27e-7 AC: 1 AN: 1078308

Other (OTH) AF: 0.00 AC: 0 AN: 57752

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Familial infantile myasthenia Uncertain:1

Jun 18, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine with alanine at codon 74 of the CHAT protein (p.Thr74Ala). The threonine residue is weakly conserved and there is a small physicochemical difference between threonine and alanine. While this variant is not present in population databases, the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with a CHAT-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, this variant has uncertain impact on CHAT function. The available evidence is currently insufficient to determine its role 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	0.062
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	11
DANN	Benign	0.93
DEOGEN2	Benign	0.074	T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.026	N
LIST_S2	Benign	0.23	T
M_CAP	Uncertain	0.095	D
MetaRNN	Benign	0.071	T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	0.55	N
PhyloP100		-0.35
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	-0.010	N
REVEL	Benign	0.25
Sift	Benign	0.052	T
Sift4G	Benign	0.073	T
Polyphen		0.0	B
Vest4		0.067
MutPred		0.12		Loss of phosphorylation at T74 (P = 0.0042);
MVP		0.68
MPC		0.24
ClinPred		0.11	T
GERP RS		-1.2
PromoterAI		0.018	Neutral
Varity_R		0.045
gMVP		0.24
Mutation Taster		=297/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1554801418; hg19: chr10-50822455;