10-49633658-C-T

Variant names:

• chr10-49633658-C-T
• rs3793791
• NM_020549.5:c.1111+5873C>T

Variant summary

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

The NM_020549.5(CHAT):​c.1111+5873C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.858 in 152,108 control chromosomes in the GnomAD database, including 56,631 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 0.86 (56631 hom., cov: 31)
• Consequence: CHAT NM_020549.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.630
• Publications: 11 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=-0.7).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.925 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHAT	NM_020549.5	c.1111+5873C>T		intron_variant	Intron 7 of 14	ENST00000337653.7	NP_065574.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHAT	ENST00000337653.7	c.1111+5873C>T		intron_variant	Intron 7 of 14	1	NM_020549.5	ENSP00000337103.2

Frequencies

GnomAD3 genomes AF: 0.858 AC: 130435 AN: 151990 Hom.: 56618 Cov.: 31

Gnomad AFR AF: 0.764

Gnomad AMI AF: 0.963

Gnomad AMR AF: 0.743

Gnomad ASJ AF: 0.945

Gnomad EAS AF: 0.760

Gnomad SAS AF: 0.846

Gnomad FIN AF: 0.934

Gnomad MID AF: 0.921

Gnomad NFE AF: 0.931

Gnomad OTH AF: 0.871

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

GnomAD4 genome AF: 0.858 AC: 130489 AN: 152108 Hom.: 56631 Cov.: 31 AF XY: 0.856 AC XY: 63627 AN XY: 74340

African (AFR) AF: 0.763 AC: 31649 AN: 41466

American (AMR) AF: 0.742 AC: 11339 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.945 AC: 3281 AN: 3472

East Asian (EAS) AF: 0.760 AC: 3910 AN: 5146

South Asian (SAS) AF: 0.847 AC: 4082 AN: 4818

European-Finnish (FIN) AF: 0.934 AC: 9909 AN: 10604

Middle Eastern (MID) AF: 0.912 AC: 268 AN: 294

European-Non Finnish (NFE) AF: 0.931 AC: 63340 AN: 68000

Other (OTH) AF: 0.867 AC: 1833 AN: 2114

Alfa AF: 0.891 Hom.: 151646

Bravo AF: 0.835

Asia WGS AF: 0.787 AC: 2739 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	8.0
DANN	Benign	0.62
PhyloP100		-0.63
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: rs3793791; hg19: chr10-50841704;