rs8178990

chr10-49622125-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_020549.5(CHAT):c.727C>T(p.Leu243Phe) variant causes a missense change. The variant allele was found at a frequency of 0.0566 in 1,610,118 control chromosomes in the GnomAD database, including 3,079 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.046 (253 hom., cov: 33)
  • Exomes 𝑓: 0.058 (2826 hom.)
• Consequence: CHAT NM_020549.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 4.05

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003634721).
• BP6: Variant 10-49622125-C-T is Benign according to our data. Variant chr10-49622125-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 128726.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-49622125-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0642 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHAT	NM_020549.5	c.727C>T	p.Leu243Phe	missense_variant	5/15	ENST00000337653.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHAT	ENST00000337653.7	c.727C>T	p.Leu243Phe	missense_variant	5/15	1	NM_020549.5	P2

Frequencies

GnomAD3 genomes AF: 0.0458 AC: 6933 AN: 151280 Hom.: 253 Cov.: 33

Gnomad AFR AF: 0.0101

Gnomad AMI AF: 0.0960

Gnomad AMR AF: 0.0307

Gnomad ASJ AF: 0.0607

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0131

Gnomad FIN AF: 0.110

Gnomad MID AF: 0.0194

Gnomad NFE AF: 0.0658

Gnomad OTH AF: 0.0352

GnomAD3 exomes AF: 0.0468 AC: 11764 AN: 251386 Hom.: 422 AF XY: 0.0462 AC XY: 6282 AN XY: 135854

Gnomad AFR exome AF: 0.00855

Gnomad AMR exome AF: 0.0227

Gnomad ASJ exome AF: 0.0555

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0115

Gnomad FIN exome AF: 0.112

Gnomad NFE exome AF: 0.0635

Gnomad OTH exome AF: 0.0484

GnomAD4 exome AF: 0.0577 AC: 84233 AN: 1458722 Hom.: 2826 Cov.: 38 AF XY: 0.0566 AC XY: 41108 AN XY: 725782

Gnomad4 AFR exome AF: 0.00796

Gnomad4 AMR exome AF: 0.0210

Gnomad4 ASJ exome AF: 0.0549

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0126

Gnomad4 FIN exome AF: 0.108

Gnomad4 NFE exome AF: 0.0644

Gnomad4 OTH exome AF: 0.0530

GnomAD4 genome AF: 0.0458 AC: 6932 AN: 151396 Hom.: 253 Cov.: 33 AF XY: 0.0466 AC XY: 3449 AN XY: 74012

Gnomad4 AFR AF: 0.0101

Gnomad4 AMR AF: 0.0307

Gnomad4 ASJ AF: 0.0607

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0133

Gnomad4 FIN AF: 0.110

Gnomad4 NFE AF: 0.0658

Gnomad4 OTH AF: 0.0348

Alfa AF: 0.0569 Hom.: 707

Bravo AF: 0.0376

TwinsUK AF: 0.0620 AC: 230

ALSPAC AF: 0.0649 AC: 250

ESP6500AA AF: 0.0111 AC: 49

ESP6500EA AF: 0.0635 AC: 546

ExAC AF: 0.0466 AC: 5663

Asia WGS AF: 0.00924 AC: 32 AN: 3476

EpiCase AF: 0.0600

EpiControl AF: 0.0602

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 28, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -
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. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 26, 2019	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 19, 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. -

Familial infantile myasthenia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

not provided Benign:1

Benign, no assertion criteria provided

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Feb 24, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.38
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Uncertain	-0.040
Cadd	Pathogenic	26
Dann	Uncertain	1.0
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.85	D
MetaRNN	Benign	0.0036	T;T;T;T;T
MetaSVM	Benign	-0.29	T
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Benign	0.42	T
PROVEAN	Uncertain	-3.3	D;D;D;D;D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0030	D;D;D;D;D
Sift4G	Uncertain	0.0090	D;D;D;D;D
Polyphen		1.0	.;.;.;D;.
Vest4		0.30
MPC		0.93
ClinPred		0.030	T
GERP RS		4.7
Varity_R		0.69
gMVP		0.58

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: rs8178990; hg19: chr10-50830171; COSMIC: COSV60324796; COSMIC: COSV60324796;