NM_020549.5:c.1635-737T>C

Variant names:

• chr10-49654358-T-C
• rs4838547
• NM_020549.5:c.1635-737T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_020549.5(CHAT):​c.1635-737T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.433 in 152,082 control chromosomes in the GnomAD database, including 14,541 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 0.43 (14541 hom., cov: 34)
• Consequence: CHAT NM_020549.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.273
• Publications: 7 publications found

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.673 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHAT	NM_020549.5	c.1635-737T>C		intron_variant	Intron 11 of 14	ENST00000337653.7	NP_065574.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHAT	ENST00000337653.7	c.1635-737T>C		intron_variant	Intron 11 of 14	1	NM_020549.5	ENSP00000337103.2

Frequencies

GnomAD3 genomes AF: 0.433 AC: 65824 AN: 151964 Hom.: 14531 Cov.: 34

Gnomad AFR AF: 0.404

Gnomad AMI AF: 0.338

Gnomad AMR AF: 0.393

Gnomad ASJ AF: 0.406

Gnomad EAS AF: 0.691

Gnomad SAS AF: 0.548

Gnomad FIN AF: 0.343

Gnomad MID AF: 0.443

Gnomad NFE AF: 0.449

Gnomad OTH AF: 0.425

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

GnomAD4 genome AF: 0.433 AC: 65869 AN: 152082 Hom.: 14541 Cov.: 34 AF XY: 0.430 AC XY: 31992 AN XY: 74346

African (AFR) AF: 0.404 AC: 16770 AN: 41466

American (AMR) AF: 0.392 AC: 5995 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.406 AC: 1408 AN: 3470

East Asian (EAS) AF: 0.692 AC: 3574 AN: 5168

South Asian (SAS) AF: 0.550 AC: 2653 AN: 4826

European-Finnish (FIN) AF: 0.343 AC: 3632 AN: 10586

Middle Eastern (MID) AF: 0.446 AC: 131 AN: 294

European-Non Finnish (NFE) AF: 0.449 AC: 30503 AN: 67964

Other (OTH) AF: 0.424 AC: 895 AN: 2110

Alfa AF: 0.445 Hom.: 35482

Bravo AF: 0.432

Asia WGS AF: 0.603 AC: 2100 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	4.3
DANN	Benign	0.69
PhyloP100		-0.27
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4838547; hg19: chr10-50862404;