rs8178991

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_020549.5(CHAT):c.1198G>A(p.Asp400Asn) variant causes a missense change. The variant allele was found at a frequency of 0.018 in 1,614,240 control chromosomes in the GnomAD database, including 344 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.012 ( 14 hom., cov: 33)

Exomes 𝑓: 0.019 ( 330 hom. )

Consequence

CHAT
NM_020549.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 4.21

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=0.007253796).

BP6

Variant 10-49646591-G-A is Benign according to our data. Variant chr10-49646591-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 128717.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-49646591-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0121 (1845/152362) while in subpopulation NFE AF= 0.0188 (1279/68034). AF 95% confidence interval is 0.0179. There are 14 homozygotes in gnomad4. There are 875 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHAT	NM_020549.5 linkuse as main transcript	c.1198G>A	p.Asp400Asn	missense_variant	8/15	ENST00000337653.7	NP_065574.4	P28329-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHAT	ENST00000337653.7 linkuse as main transcript	c.1198G>A	p.Asp400Asn	missense_variant	8/15	1	NM_020549.5	ENSP00000337103.2		P28329-1

Frequencies

GnomAD3 genomes

AF:

0.0121

AC:

1845

AN:

152244

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00345

Gnomad AMI

AF:

0.0395

Gnomad AMR

AF:

0.00621

Gnomad ASJ

AF:

0.00634

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00290

Gnomad FIN

AF:

0.0219

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0188

Gnomad OTH

AF:

0.0100

GnomAD3 exomes

AF:

0.0131

AC:

3287

AN:

251338

Hom.:

AF XY:

0.0131

AC XY:

1782

AN XY:

135880

show subpopulations

Gnomad AFR exome

AF:

0.00382

Gnomad AMR exome

AF:

0.00607

Gnomad ASJ exome

AF:

0.0109

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.00327

Gnomad FIN exome

AF:

0.0223

Gnomad NFE exome

AF:

0.0197

Gnomad OTH exome

AF:

0.0140

GnomAD4 exome

AF:

0.0186

AC:

27186

AN:

1461878

Hom.:

330

Cov.:

AF XY:

0.0180

AC XY:

13057

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.00299

Gnomad4 AMR exome

AF:

0.00628

Gnomad4 ASJ exome

AF:

0.00918

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.00348

Gnomad4 FIN exome

AF:

0.0228

Gnomad4 NFE exome

AF:

0.0217

Gnomad4 OTH exome

AF:

0.0144

GnomAD4 genome

AF:

0.0121

AC:

1845

AN:

152362

Hom.:

Cov.:

AF XY:

0.0117

AC XY:

875

AN XY:

74508

show subpopulations

Gnomad4 AFR

AF:

0.00344

Gnomad4 AMR

AF:

0.00621

Gnomad4 ASJ

AF:

0.00634

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00290

Gnomad4 FIN

AF:

0.0219

Gnomad4 NFE

AF:

0.0188

Gnomad4 OTH

AF:

0.00992

Alfa

AF:

0.0158

Hom.:

Bravo

AF:

0.0117

TwinsUK

AF:

0.0224

AC:

ALSPAC

AF:

0.0171

AC:

ESP6500AA

AF:

0.00477

AC:

ESP6500EA

AF:

0.0220

AC:

189

ExAC

AF:

0.0133

AC:

1617

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.0154

EpiControl

AF:

0.0177

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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. -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 20, 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:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 23, 2016	- -

Familial infantile myasthenia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.39

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.43

.;.;.;T;.;.

Eigen

Uncertain

0.29

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.91

.;.;D;D;D;D

MetaRNN

Benign

0.0073

T;T;T;T;T;T

MetaSVM

Uncertain

-0.21

MutationAssessor

Benign

1.5

.;.;.;L;.;.

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-1.9

N;N;N;N;N;.

REVEL

Uncertain

0.33

Sift

Benign

0.055

T;T;T;T;T;.

Sift4G

Benign

0.081

T;T;T;T;T;.

Polyphen

0.98

.;.;.;D;.;.

Vest4

0.19

MPC

0.43

ClinPred

0.013

GERP RS

4.3

Varity_R

0.33

gMVP

0.67

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

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