Genetic Variant NM_020549.5:c.1112-1025T>C (chr10-49645480-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_020549.5(CHAT):c.1112-1025T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.851 in 152,200 control chromosomes in the GnomAD database, including 55,723 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.85 ( 55723 hom., cov: 33)

Consequence

CHAT
NM_020549.5 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.73

Publications

3 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: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-1.06).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.917 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHAT	NM_020549.5 link	c.1112-1025T>C		intron_variant	Intron 7 of 14	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.1112-1025T>C		intron_variant	Intron 7 of 14	1	NM_020549.5	ENSP00000337103.2		P28329-1

Frequencies

GnomAD3 genomes

AF:

0.851

AC:

129477

AN:

152082

Hom.:

55717

Cov.:

show subpopulations

Gnomad AFR

AF:

0.770

Gnomad AMI

AF:

0.895

Gnomad AMR

AF:

0.846

Gnomad ASJ

AF:

0.885

Gnomad EAS

AF:

0.565

Gnomad SAS

AF:

0.808

Gnomad FIN

AF:

0.858

Gnomad MID

AF:

0.949

Gnomad NFE

AF:

0.923

Gnomad OTH

AF:

0.875

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.851

AC:

129524

AN:

152200

Hom.:

55723

Cov.:

AF XY:

0.846

AC XY:

62948

AN XY:

74408

show subpopulations

African (AFR)

AF:

0.769

AC:

31930

AN:

41512

American (AMR)

AF:

0.845

AC:

12932

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.885

AC:

3071

AN:

3472

East Asian (EAS)

AF:

0.565

AC:

2913

AN:

5158

South Asian (SAS)

AF:

0.808

AC:

3896

AN:

4822

European-Finnish (FIN)

AF:

0.858

AC:

9094

AN:

10602

Middle Eastern (MID)

AF:

0.939

AC:

276

AN:

294

European-Non Finnish (NFE)

AF:

0.923

AC:

62762

AN:

68018

Other (OTH)

AF:

0.868

AC:

1836

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

957

1913

2870

3826

4783

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

886

1772

2658

3544

4430

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.895

Hom.:

228644

Bravo

AF:

0.844

Asia WGS

AF:

0.709

AC:

2468

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-1.1

CADD

Benign

0.031

(source)

DANN

Benign

0.16

PhyloP100

-2.7

Mutation Taster

=100/0

polymorphism (auto)

(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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over