rs80097077

chr10-49655142-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_020549.5(CHAT):c.1682G>A(p.Arg561Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0096 in 1,614,060 control chromosomes in the GnomAD database, including 87 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0081 (9 hom., cov: 32)
  • Exomes 𝑓: 0.0098 (78 hom.)
• Consequence: CHAT NM_020549.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 8.02

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 Benign. Variant got -18 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_020549.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.025550604).
• BP6: Variant 10-49655142-G-A is Benign according to our data. Variant chr10-49655142-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 128721.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-49655142-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00811 (1235/152238) while in subpopulation AMR AF= 0.0155 (237/15288). AF 95% confidence interval is 0.0139. There are 9 homozygotes in gnomad4. There are 607 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHAT	NM_020549.5	c.1682G>A	p.Arg561Gln	missense_variant	12/15	ENST00000337653.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHAT	ENST00000337653.7	c.1682G>A	p.Arg561Gln	missense_variant	12/15	1	NM_020549.5	P2

Frequencies

GnomAD3 genomes AF: 0.00812 AC: 1235 AN: 152120 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.00256

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0155

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000623

Gnomad FIN AF: 0.00669

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0111

Gnomad OTH AF: 0.0115

GnomAD3 exomes AF: 0.00750 AC: 1885 AN: 251288 Hom.: 13 AF XY: 0.00751 AC XY: 1020 AN XY: 135878

Gnomad AFR exome AF: 0.00160

Gnomad AMR exome AF: 0.00997

Gnomad ASJ exome AF: 0.00992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000359

Gnomad FIN exome AF: 0.00725

Gnomad NFE exome AF: 0.0105

Gnomad OTH exome AF: 0.00946

GnomAD4 exome AF: 0.00976 AC: 14264 AN: 1461822 Hom.: 78 Cov.: 37 AF XY: 0.00947 AC XY: 6890 AN XY: 727224

Gnomad4 AFR exome AF: 0.00164

Gnomad4 AMR exome AF: 0.0104

Gnomad4 ASJ exome AF: 0.00830

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000359

Gnomad4 FIN exome AF: 0.00826

Gnomad4 NFE exome AF: 0.0113

Gnomad4 OTH exome AF: 0.00800

GnomAD4 genome AF: 0.00811 AC: 1235 AN: 152238 Hom.: 9 Cov.: 32 AF XY: 0.00816 AC XY: 607 AN XY: 74428

Gnomad4 AFR AF: 0.00255

Gnomad4 AMR AF: 0.0155

Gnomad4 ASJ AF: 0.0101

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000623

Gnomad4 FIN AF: 0.00669

Gnomad4 NFE AF: 0.0111

Gnomad4 OTH AF: 0.0114

Alfa AF: 0.00974 Hom.: 19

Bravo AF: 0.00802

TwinsUK AF: 0.0132 AC: 49

ALSPAC AF: 0.0130 AC: 50

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.0102 AC: 88

ExAC AF: 0.00743 AC: 902

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.0110

EpiControl AF: 0.0127

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 16, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 03, 2016	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Familial infantile myasthenia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Benign	-0.055	T
BayesDel_noAF	Pathogenic	0.16
Cadd	Pathogenic	33
Dann	Pathogenic	1.0
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.99	D
MetaRNN	Benign	0.026	T;T;T;T;T;T
MetaSVM	Uncertain	0.29	D
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-2.8	D;D;D;D;D;.
REVEL	Pathogenic	0.71
Sift	Benign	0.040	D;D;D;D;D;.
Sift4G	Benign	0.069	T;T;T;D;T;.
Polyphen		1.0	.;.;.;D;.;.
Vest4		0.66
MVP		0.96
MPC		0.96
ClinPred		0.0077	T
GERP RS		5.4
Varity_R		0.75
gMVP		0.78

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: rs80097077; hg19: chr10-50863188; COSMIC: COSV104639426;