10-49618117-A-G

Variant names:

• chr10-49618117-A-G
• rs7091005
• NM_020549.5:c.387+1515A>G

Variant summary

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

The NM_020549.5(CHAT):​c.387+1515A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.909 in 152,258 control chromosomes in the GnomAD database, including 62,992 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 0.91 (62992 hom., cov: 32)
• Consequence: CHAT NM_020549.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.65
• Publications: 3 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=-0.98).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.977 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHAT	NM_020549.5	c.387+1515A>G		intron_variant	Intron 2 of 14	ENST00000337653.7	NP_065574.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHAT	ENST00000337653.7	c.387+1515A>G		intron_variant	Intron 2 of 14	1	NM_020549.5	ENSP00000337103.2

Frequencies

GnomAD3 genomes AF: 0.909 AC: 138351 AN: 152140 Hom.: 62946 Cov.: 32

Gnomad AFR AF: 0.890

Gnomad AMI AF: 0.864

Gnomad AMR AF: 0.940

Gnomad ASJ AF: 0.890

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.935

Gnomad FIN AF: 0.900

Gnomad MID AF: 0.889

Gnomad NFE AF: 0.908

Gnomad OTH AF: 0.919

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

GnomAD4 genome AF: 0.909 AC: 138455 AN: 152258 Hom.: 62992 Cov.: 32 AF XY: 0.909 AC XY: 67687 AN XY: 74438

African (AFR) AF: 0.890 AC: 36974 AN: 41530

American (AMR) AF: 0.940 AC: 14383 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.890 AC: 3086 AN: 3466

East Asian (EAS) AF: 1.00 AC: 5171 AN: 5172

South Asian (SAS) AF: 0.935 AC: 4509 AN: 4822

European-Finnish (FIN) AF: 0.900 AC: 9555 AN: 10620

Middle Eastern (MID) AF: 0.884 AC: 260 AN: 294

European-Non Finnish (NFE) AF: 0.908 AC: 61785 AN: 68028

Other (OTH) AF: 0.920 AC: 1944 AN: 2114

Alfa AF: 0.911 Hom.: 106379

Bravo AF: 0.911

Asia WGS AF: 0.962 AC: 3348 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	0.35
DANN	Benign	0.62
PhyloP100		-1.6
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: rs7091005; hg19: chr10-50826163;