Genetic Variant CHAT:c.-68-3357G>T (chr10-49613145-G-T) – 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_020985.4(CHAT):c.-298G>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.551 in 152,156 control chromosomes in the GnomAD database, including 28,199 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.55 ( 28178 hom., cov: 33)

Exomes 𝑓: 0.70 ( 21 hom. )

Consequence

CHAT
NM_020985.4 5_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.00500

Publications

12 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=-0.81).

BP6

Variant 10-49613145-G-T is Benign according to our data. Variant chr10-49613145-G-T is described in ClinVar as Benign. ClinVar VariationId is 1255202.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.76 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020985.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	HGVSc	Effect	Exon Rank	Protein	UniProt
CHAT	NM_020985.4	c.-298G>T	5_prime_UTR	Exon 1 of 16	NP_066265.4	P28329-3
CHAT	NM_020986.4	c.-126G>T	5_prime_UTR	Exon 1 of 15	NP_066266.4	P28329-3
CHAT	NM_020984.4	c.-68-3357G>T	intron	N/A	NP_066264.4	P28329-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
CHAT	ENST00000339797.5	TSL:1	c.-68-3357G>T	intron	N/A	ENSP00000343486.1	P28329-3
CHAT	ENST00000460699.5	TSL:1	n.38G>T	non_coding_transcript_exon	Exon 1 of 7
CHAT	ENST00000481336.5	TSL:1	n.27G>T	non_coding_transcript_exon	Exon 1 of 3

Frequencies

GnomAD3 genomes

AF:

0.551

AC:

83799

AN:

151952

Hom.:

28193

Cov.:

show subpopulations

Gnomad AFR

AF:

0.176

Gnomad AMI

AF:

0.778

Gnomad AMR

AF:

0.499

Gnomad ASJ

AF:

0.698

Gnomad EAS

AF:

0.312

Gnomad SAS

AF:

0.758

Gnomad FIN

AF:

0.664

Gnomad MID

AF:

0.677

Gnomad NFE

AF:

0.765

Gnomad OTH

AF:

0.592

GnomAD4 exome

AF:

0.698

AC:

AN:

Hom.:

Cov.:

AF XY:

0.734

AC XY:

AN XY:

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

American (AMR)

AF:

0.00

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AF:

0.333

AC:

AN:

South Asian (SAS)

AF:

1.00

AC:

AN:

European-Finnish (FIN)

AF:

1.00

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.750

AC:

AN:

Other (OTH)

AF:

0.667

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Hom

Variant carriers

<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:

0.551

AC:

83770

AN:

152070

Hom.:

28178

Cov.:

AF XY:

0.548

AC XY:

40768

AN XY:

74348

show subpopulations

African (AFR)

AF:

0.176

AC:

7284

AN:

41486

American (AMR)

AF:

0.498

AC:

7615

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.698

AC:

2421

AN:

3468

East Asian (EAS)

AF:

0.312

AC:

1605

AN:

5152

South Asian (SAS)

AF:

0.759

AC:

3660

AN:

4822

European-Finnish (FIN)

AF:

0.664

AC:

7024

AN:

10578

Middle Eastern (MID)

AF:

0.663

AC:

195

AN:

294

European-Non Finnish (NFE)

AF:

0.765

AC:

52022

AN:

67966

Other (OTH)

AF:

0.587

AC:

1238

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1442

2884

4327

5769

7211

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

682

1364

2046

2728

3410

<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:

0.669

Hom.:

84337

Bravo

AF:

0.511

Asia WGS

AF:

0.493

AC:

1717

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.81

CADD

Benign

6.6

(source)

DANN

Benign

0.88

PhyloP100

0.0050

PromoterAI

-0.023

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

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