rs3810950

Positions:

chr10-49616573-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_020549.5(CHAT):c.358G>A(p.Ala120Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.237 in 1,610,550 control chromosomes in the GnomAD database, including 47,769 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.18 ( 3040 hom., cov: 33)

Exomes 𝑓: 0.24 ( 44729 hom. )

Consequence

CHAT
NM_020549.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 1.34

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003578037).

BP6

Variant 10-49616573-G-A is Benign according to our data. Variant chr10-49616573-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 128724.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-49616573-G-A is described in Lovd as [Benign]. Variant chr10-49616573-G-A is described in Lovd as [Pathogenic].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.26 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHAT	NM_020549.5 linkuse as main transcript	c.358G>A	p.Ala120Thr	missense_variant	2/15	ENST00000337653.7	NP_065574.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHAT	ENST00000337653.7 linkuse as main transcript	c.358G>A	p.Ala120Thr	missense_variant	2/15	1	NM_020549.5	ENSP00000337103	P2	P28329-1

Frequencies

GnomAD3 genomes

AF:

0.180

AC:

27291

AN:

152026

Hom.:

3042

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0483

Gnomad AMI

AF:

0.268

Gnomad AMR

AF:

0.185

Gnomad ASJ

AF:

0.234

Gnomad EAS

AF:

0.158

Gnomad SAS

AF:

0.273

Gnomad FIN

AF:

0.182

Gnomad MID

AF:

0.217

Gnomad NFE

AF:

0.249

Gnomad OTH

AF:

0.191

GnomAD3 exomes

AF:

0.207

AC:

51237

AN:

247220

Hom.:

5826

AF XY:

0.218

AC XY:

29048

AN XY:

133496

show subpopulations

Gnomad AFR exome

AF:

0.0412

Gnomad AMR exome

AF:

0.143

Gnomad ASJ exome

AF:

0.243

Gnomad EAS exome

AF:

0.145

Gnomad SAS exome

AF:

0.273

Gnomad FIN exome

AF:

0.179

Gnomad NFE exome

AF:

0.244

Gnomad OTH exome

AF:

0.227

GnomAD4 exome

AF:

0.243

AC:

354143

AN:

1458404

Hom.:

44729

Cov.:

AF XY:

0.245

AC XY:

177619

AN XY:

725372

show subpopulations

Gnomad4 AFR exome

AF:

0.0391

Gnomad4 AMR exome

AF:

0.149

Gnomad4 ASJ exome

AF:

0.246

Gnomad4 EAS exome

AF:

0.173

Gnomad4 SAS exome

AF:

0.276

Gnomad4 FIN exome

AF:

0.186

Gnomad4 NFE exome

AF:

0.256

Gnomad4 OTH exome

AF:

0.235

GnomAD4 genome

AF:

0.179

AC:

27284

AN:

152146

Hom.:

3040

Cov.:

AF XY:

0.179

AC XY:

13322

AN XY:

74342

show subpopulations

Gnomad4 AFR

AF:

0.0482

Gnomad4 AMR

AF:

0.185

Gnomad4 ASJ

AF:

0.234

Gnomad4 EAS

AF:

0.157

Gnomad4 SAS

AF:

0.273

Gnomad4 FIN

AF:

0.182

Gnomad4 NFE

AF:

0.249

Gnomad4 OTH

AF:

0.190

Alfa

AF:

0.239

Hom.:

8666

Bravo

AF:

0.171

TwinsUK

AF:

0.257

AC:

953

ALSPAC

AF:

0.273

AC:

1054

ESP6500AA

AF:

0.0517

AC:

228

ESP6500EA

AF:

0.249

AC:

2144

ExAC

AF:

0.207

AC:

25173

Asia WGS

AF:

0.191

AC:

664

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Feb 01, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 22, 2013	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 03, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 04, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 11, 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. -
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: MAF -

Familial infantile myasthenia

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided

Benign:2

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 11, 2016	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.35

CADD

Benign

DANN

Benign

0.84

DEOGEN2

Benign

0.070

.;.;.;T;.

Eigen

Benign

-0.78

Eigen_PC

Benign

-0.72

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.58

.;.;T;T;T

MetaRNN

Benign

0.0036

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.69

.;.;.;N;.

MutationTaster

Benign

1.0

P;P;P;P;P;P

PrimateAI

Benign

0.30

PROVEAN

Benign

0.030

N;N;N;N;N

REVEL

Benign

0.10

Sift

Benign

0.13

T;T;T;T;T

Sift4G

Benign

0.12

T;T;T;T;T

Polyphen

0.014

.;.;.;B;.

Vest4

0.22

MPC

0.24

ClinPred

0.0033

GERP RS

3.0

Varity_R

0.026

gMVP

0.17

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over