rs4838544

Positions:

Variant summary

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

The NM_020549.5(CHAT):c.1381G>A(p.Val461Met) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.994 in 1,609,818 control chromosomes in the GnomAD database, including 795,386 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V461A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.97 ( 71526 hom., cov: 32)

Exomes 𝑓: 1.0 ( 723860 hom. )

Consequence

CHAT
NM_020549.5 missense, splice_region

Scores

Splicing: ADA: 0.00002959

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 5.30

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=6.5965037E-7).

BP6

Variant 10-49648606-G-A is Benign according to our data. Variant chr10-49648606-G-A is described in ClinVar as [Benign]. Clinvar id is 199157.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-49648606-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHAT	NM_020549.5 linkuse as main transcript	c.1381G>A	p.Val461Met	missense_variant, splice_region_variant	9/15	ENST00000337653.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHAT	ENST00000337653.7 linkuse as main transcript	c.1381G>A	p.Val461Met	missense_variant, splice_region_variant	9/15	1	NM_020549.5	P2	P28329-1

Frequencies

GnomAD3 genomes

AF:

0.968

AC:

147239

AN:

152126

Hom.:

71478

Cov.:

show subpopulations

Gnomad AFR

AF:

0.887

Gnomad AMI

AF:

1.00

Gnomad AMR

AF:

0.991

Gnomad ASJ

AF:

0.998

Gnomad EAS

AF:

1.00

Gnomad SAS

AF:

1.00

Gnomad FIN

AF:

1.00

Gnomad MID

AF:

1.00

Gnomad NFE

AF:

1.00

Gnomad OTH

AF:

0.979

GnomAD3 exomes

AF:

0.991

AC:

246545

AN:

248716

Hom.:

122287

AF XY:

0.994

AC XY:

133709

AN XY:

134570

show subpopulations

Gnomad AFR exome

AF:

0.884

Gnomad AMR exome

AF:

0.993

Gnomad ASJ exome

AF:

0.999

Gnomad EAS exome

AF:

1.00

Gnomad SAS exome

AF:

1.00

Gnomad FIN exome

AF:

1.00

Gnomad NFE exome

AF:

1.00

Gnomad OTH exome

AF:

0.995

GnomAD4 exome

AF:

0.996

AC:

1452385

AN:

1457574

Hom.:

723860

Cov.:

AF XY:

0.997

AC XY:

722972

AN XY:

725220

show subpopulations

Gnomad4 AFR exome

AF:

0.882

Gnomad4 AMR exome

AF:

0.993

Gnomad4 ASJ exome

AF:

0.999

Gnomad4 EAS exome

AF:

1.00

Gnomad4 SAS exome

AF:

1.00

Gnomad4 FIN exome

AF:

1.00

Gnomad4 NFE exome

AF:

1.00

Gnomad4 OTH exome

AF:

0.993

GnomAD4 genome

AF:

0.968

AC:

147345

AN:

152244

Hom.:

71526

Cov.:

AF XY:

0.969

AC XY:

72135

AN XY:

74430

show subpopulations

Gnomad4 AFR

AF:

0.887

Gnomad4 AMR

AF:

0.991

Gnomad4 ASJ

AF:

0.998

Gnomad4 EAS

AF:

1.00

Gnomad4 SAS

AF:

1.00

Gnomad4 FIN

AF:

1.00

Gnomad4 NFE

AF:

1.00

Gnomad4 OTH

AF:

0.980

Alfa

AF:

0.997

Hom.:

135694

Bravo

AF:

0.963

TwinsUK

AF:

1.00

AC:

3708

ALSPAC

AF:

1.00

AC:

3853

ESP6500AA

AF:

0.886

AC:

3905

ESP6500EA

AF:

0.999

AC:

8594

ExAC

AF:

0.989

AC:

120061

Asia WGS

AF:

0.994

AC:

3456

AN:

3478

EpiCase

AF:

0.999

EpiControl

AF:

0.999

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Familial infantile myasthenia

Benign:3

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 22, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 21, 2014	- -
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 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.30

CADD

Benign

DANN

Benign

0.077

DEOGEN2

Benign

0.18

.;.;.;T;.;.

Eigen

Benign

-0.82

Eigen_PC

Benign

-0.57

FATHMM_MKL

Benign

0.24

LIST_S2

Benign

0.17

.;.;T;T;T;T

MetaRNN

Benign

6.6e-7

T;T;T;T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

-1.5

.;.;.;N;.;.

MutationTaster

Benign

1.0

P;P;P;P;P;P

PrimateAI

Benign

0.47

PROVEAN

Benign

0.97

N;N;N;N;N;.

REVEL

Benign

0.26

Sift

Benign

1.0

T;T;T;T;T;.

Sift4G

Benign

1.0

T;T;T;T;T;.

Polyphen

0.048

.;.;.;B;.;.

Vest4

0.031

MPC

0.25

ClinPred

0.0036

GERP RS

3.9

Varity_R

0.071

gMVP

0.46

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000030

dbscSNV1_RF

Benign

0.016

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

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