10-49608897-C-T

Variant names:

• chr10-49608897-C-T
• rs733722
• ENST00000339797.5:c.-371C>T

Variant summary

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

The ENST00000339797.5(CHAT):​c.-371C>T variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.221 in 152,022 control chromosomes in the GnomAD database, including 4,327 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 0.22 (4327 hom., cov: 32)
• Consequence: CHAT ENST00000339797.5 upstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.460
• Publications: 13 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=-0.78).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.434 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHAT	NM_020984.4	c.-371C>T		upstream_gene_variant			NP_066264.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHAT	ENST00000339797.5	c.-371C>T		upstream_gene_variant		1		ENSP00000343486.1

Frequencies

GnomAD3 genomes AF: 0.221 AC: 33584 AN: 151904 Hom.: 4308 Cov.: 32

Gnomad AFR AF: 0.185

Gnomad AMI AF: 0.232

Gnomad AMR AF: 0.375

Gnomad ASJ AF: 0.166

Gnomad EAS AF: 0.449

Gnomad SAS AF: 0.244

Gnomad FIN AF: 0.203

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.196

Gnomad OTH AF: 0.214

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

GnomAD4 genome AF: 0.221 AC: 33643 AN: 152022 Hom.: 4327 Cov.: 32 AF XY: 0.226 AC XY: 16814 AN XY: 74308

African (AFR) AF: 0.185 AC: 7666 AN: 41498

American (AMR) AF: 0.375 AC: 5727 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.166 AC: 576 AN: 3468

East Asian (EAS) AF: 0.449 AC: 2301 AN: 5120

South Asian (SAS) AF: 0.244 AC: 1171 AN: 4808

European-Finnish (FIN) AF: 0.203 AC: 2147 AN: 10576

Middle Eastern (MID) AF: 0.143 AC: 42 AN: 294

European-Non Finnish (NFE) AF: 0.196 AC: 13338 AN: 67982

Other (OTH) AF: 0.221 AC: 465 AN: 2106

Alfa AF: 0.208 Hom.: 5989

Bravo AF: 0.240

Asia WGS AF: 0.332 AC: 1151 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	6.2
DANN	Benign	0.84
PhyloP100		0.46
PromoterAI		-0.0044	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs733722; hg19: chr10-50816943;