10-49649569-A-G

Position:

• chr10-49649569-A-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2 PP3_Moderate PP5_Very_Strong

The NM_020549.5(CHAT):​c.1444A>G​(p.Arg482Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,538 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 Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CHAT NM_020549.5 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 4.58

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.928
• PP5: Variant 10-49649569-A-G is Pathogenic according to our data. Variant chr10-49649569-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 17509.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-49649569-A-G is described in Lovd as [Pathogenic]. Variant chr10-49649569-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHAT	NM_020549.5	c.1444A>G	p.Arg482Gly	missense_variant	10/15	ENST00000337653.7	NP_065574.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHAT	ENST00000337653.7	c.1444A>G	p.Arg482Gly	missense_variant	10/15	1	NM_020549.5	ENSP00000337103.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461538 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727076

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000381 Hom.: 0

Bravo AF: 0.00000378

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial infantile myasthenia Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 06, 2020	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CHAT protein function. This variant has been observed in individual(s) with congenital myasthenic syndrome (PMID: 11172068, 19900826). ClinVar contains an entry for this variant (Variation ID: 17509). This variant is not present in population databases (ExAC no frequency). This sequence change replaces arginine with glycine at codon 482 of the CHAT protein (p.Arg482Gly). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and glycine. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 13, 2001	- -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Dec 01, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.87
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.84	.;.;.;D;.;.
Eigen	Pathogenic	0.68
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	.;.;D;D;D;D
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D;D
MetaSVM	Uncertain	0.76	D
MutationAssessor	Pathogenic	3.2	.;.;.;M;.;.
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-5.4	D;D;D;D;D;.
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0020	D;D;D;D;D;.
Sift4G	Uncertain	0.0080	D;D;D;D;D;.
Polyphen		1.0	.;.;.;D;.;.
Vest4		0.93
MutPred		0.77		.;.;.;Loss of stability (P = 0.04);.;.;
MVP		0.94
MPC		1.0
ClinPred		1.0	D
GERP RS		5.0
Varity_R		0.92
gMVP		0.82

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

Publications

LitVar

Other links and lift over

dbSNP: rs121912818; hg19: chr10-50857615;