rs4838392

Variant names:

• chr10-49626932-A-G
• rs4838392
• NM_020549.5:c.934-676A>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.934-676A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.341 in 152,266 control chromosomes in the GnomAD database, including 9,843 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 0.34 (9843 hom., cov: 34)
• Consequence: CHAT NM_020549.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.161
• Publications: 4 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=-0.82).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.534 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020549.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHAT	NM_020549.5	MANE Select	c.934-676A>G		intron	N/A	NP_065574.4
	CHAT	NM_001142933.2		c.688-676A>G		intron	N/A	NP_001136405.2
	CHAT	NM_001142929.2		c.580-676A>G		intron	N/A	NP_001136401.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHAT	ENST00000337653.7	TSL:1 MANE Select	c.934-676A>G		intron	N/A	ENSP00000337103.2
	CHAT	ENST00000395562.2	TSL:1	c.688-676A>G		intron	N/A	ENSP00000378929.2
	CHAT	ENST00000339797.5	TSL:1	c.580-676A>G		intron	N/A	ENSP00000343486.1

Frequencies

GnomAD3 genomes AF: 0.341 AC: 51857 AN: 152146 Hom.: 9852 Cov.: 34

Gnomad AFR AF: 0.166

Gnomad AMI AF: 0.455

Gnomad AMR AF: 0.331

Gnomad ASJ AF: 0.419

Gnomad EAS AF: 0.551

Gnomad SAS AF: 0.305

Gnomad FIN AF: 0.485

Gnomad MID AF: 0.446

Gnomad NFE AF: 0.407

Gnomad OTH AF: 0.363

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

GnomAD4 genome AF: 0.341 AC: 51847 AN: 152266 Hom.: 9843 Cov.: 34 AF XY: 0.342 AC XY: 25504 AN XY: 74466

African (AFR) AF: 0.166 AC: 6905 AN: 41558

American (AMR) AF: 0.330 AC: 5054 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.419 AC: 1455 AN: 3472

East Asian (EAS) AF: 0.551 AC: 2852 AN: 5176

South Asian (SAS) AF: 0.304 AC: 1470 AN: 4830

European-Finnish (FIN) AF: 0.485 AC: 5142 AN: 10598

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

European-Non Finnish (NFE) AF: 0.407 AC: 27663 AN: 68008

Other (OTH) AF: 0.360 AC: 761 AN: 2116

Alfa AF: 0.381 Hom.: 36854

Bravo AF: 0.327

Asia WGS AF: 0.350 AC: 1216 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.3
DANN	Benign	0.71
PhyloP100		-0.16
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: rs4838392; hg19: chr10-50834978;