dbSNP rs77152496: CHAT:c.-17G>A (chr10-49614173-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_020549.5(CHAT):c.-17G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00314 in 1,544,524 control chromosomes in the GnomAD database, including 145 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.016 ( 86 hom., cov: 28)

Exomes 𝑓: 0.0017 ( 59 hom. )

Consequence

CHAT
NM_020549.5 5_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.0340

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: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant 10-49614173-G-A is Benign according to our data. Variant chr10-49614173-G-A is described in ClinVar as Benign. ClinVar VariationId is 193434.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0547 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020549.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CHAT	NM_020549.5	MANE Select	c.-17G>A	5_prime_UTR	Exon 1 of 15	NP_065574.4	P28329-1
CHAT	NM_001142933.2		c.-333G>A	5_prime_UTR	Exon 1 of 16	NP_001136405.2	P28329-2
CHAT	NM_001142929.2		c.-371G>A	5_prime_UTR	Exon 1 of 15	NP_001136401.2	P28329-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CHAT	ENST00000337653.7	TSL:1 MANE Select	c.-17G>A	5_prime_UTR	Exon 1 of 15	ENSP00000337103.2	P28329-1
CHAT	ENST00000395562.2	TSL:1	c.-333G>A	5_prime_UTR	Exon 1 of 16	ENSP00000378929.2	P28329-2
CHAT	ENST00000339797.5	TSL:1	c.-68-2329G>A	intron	N/A	ENSP00000343486.1	P28329-3

Frequencies

GnomAD3 genomes

AF:

0.0162

AC:

2457

AN:

151526

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0565

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00650

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.000209

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.0111

GnomAD2 exomes

AF:

0.00337

AC:

480

AN:

142228

AF XY:

0.00287

show subpopulations

Gnomad AFR exome

AF:

0.0608

Gnomad AMR exome

AF:

0.00308

Gnomad ASJ exome

AF:

0.000122

Gnomad EAS exome

AF:

0.000189

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000214

Gnomad OTH exome

AF:

0.00145

GnomAD4 exome

AF:

0.00172

AC:

2390

AN:

1392882

Hom.:

Cov.:

AF XY:

0.00148

AC XY:

1018

AN XY:

687072

show subpopulations

African (AFR)

AF:

0.0588

AC:

1852

AN:

31508

American (AMR)

AF:

0.00361

AC:

127

AN:

35200

Ashkenazi Jewish (ASJ)

AF:

0.0000398

AC:

AN:

25124

East Asian (EAS)

AF:

0.0000280

AC:

AN:

35718

South Asian (SAS)

AF:

0.000316

AC:

AN:

79108

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47292

Middle Eastern (MID)

AF:

0.00267

AC:

AN:

4118

European-Non Finnish (NFE)

AF:

0.000129

AC:

139

AN:

1077094

Other (OTH)

AF:

0.00405

AC:

234

AN:

57720

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

118

236

353

471

589

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

124

186

248

310

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0163

AC:

2467

AN:

151642

Hom.:

Cov.:

AF XY:

0.0154

AC XY:

1141

AN XY:

74118

show subpopulations

African (AFR)

AF:

0.0566

AC:

2332

AN:

41204

American (AMR)

AF:

0.00649

AC:

AN:

15248

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.000194

AC:

AN:

5144

South Asian (SAS)

AF:

0.000210

AC:

AN:

4770

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10584

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000162

AC:

AN:

67926

Other (OTH)

AF:

0.0110

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

109

218

327

436

545

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

130

<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:

0.00830

Hom.:

Bravo

AF:

0.0189

Asia WGS

AF:

0.00231

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

2.5

(source)

DANN

Benign

0.82

PhyloP100

0.034

PromoterAI

-0.0088

Neutral

(source)

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over