Genetic Variant CHAT:p.Ala307Val (chr10-49625640-C-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_020549.5(CHAT):c.920C>T(p.Ala307Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000141 in 1,420,466 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A307G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CHAT
NM_020549.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.15

Publications

1 publications found

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 Gene-Disease associations (from GenCC):

congenital myasthenic syndrome 6
Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
presynaptic congenital myasthenic syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

CHAT links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.37383577).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHAT	NM_020549.5 link	c.920C>T	p.Ala307Val	missense_variant	Exon 6 of 15	ENST00000337653.7	NP_065574.4	P28329-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHAT	ENST00000337653.7 link	c.920C>T	p.Ala307Val	missense_variant	Exon 6 of 15	1	NM_020549.5	ENSP00000337103.2		P28329-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000110

AC:

AN:

182644

AF XY:

0.0000207

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000141

AC:

AN:

1420466

Hom.:

Cov.:

AF XY:

0.00000285

AC XY:

AN XY:

702692

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32596

American (AMR)

AF:

0.00

AC:

AN:

38348

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25378

East Asian (EAS)

AF:

0.00

AC:

AN:

37710

South Asian (SAS)

AF:

0.0000246

AC:

AN:

81272

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50640

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5726

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1089904

Other (OTH)

AF:

0.00

AC:

AN:

58892

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000837

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.34

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.070

CADD

Benign

(source)

DANN

Benign

0.83

DEOGEN2

Benign

0.20

.;.;.;T;.

Eigen

Benign

-0.088

Eigen_PC

Benign

0.045

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.95

.;.;D;D;D

M_CAP

Benign

0.053

MetaRNN

Benign

0.37

T;T;T;T;T

MetaSVM

Uncertain

-0.27

MutationAssessor

Benign

1.4

.;.;.;L;.

PhyloP100

6.2

PrimateAI

Uncertain

0.70

PROVEAN

Benign

0.13

N;N;N;N;N

REVEL

Uncertain

0.59

Sift

Benign

1.0

T;T;T;T;T

Sift4G

Benign

1.0

T;T;T;T;T

Polyphen

0.80

.;.;.;P;.

Vest4

0.50

MutPred

0.48

.;.;.;Loss of sheet (P = 0.1501);.;

MVP

0.90

MPC

0.32

ClinPred

0.30

GERP RS

5.3

Varity_R

0.54

gMVP

0.59

Mutation Taster

=10/90

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over